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https://chemwiki.ch.ic.ac.uk/index.php?title=It:Retinal&diff=4981
It:Retinal
2006-11-07T11:19:47Z
<p>Qlw05: /* Structure of all-trans retinal */</p>
<hr />
<div>__toc__<br />
<br />
'''Retinal''', also known as retinaldehyde or retinene<sub>1</sub> is the most important molecule associated with vision. Retinal changes structure when it is exposed to light, essentially transferring the energy from the light it absorbs to an electrical impulse in the retina of the eye, which is then passed along the optic nerve to the central nervous system to be processed. All vision systems operate in this manner, so Retinal is resposible for all vision. Retinal is a retinine molecule that exists as two different isomers - 11-cis retinal and all-trans retinal.<br />
<br />
== Structure of Cis-Retinal ==<br />
<br />
{| class="toccolours" border="0" style="fix: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" bgcolor="lt blue"|'''2D Structure'''<br />
| align="center" bgcolor="lt blue"|'''3D Structure'''<br />
|-<br />
| [[image:Cis-RetinalSo.gif]]<br />
|<jmol><br />
<jmolApplet><br />
<size>350</size><br />
<color>white</color><br />
<script>zoom 100; bns on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
HEADER NONAME 23-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 23-Oct-06 0 NONE 4<br />
ATOM 1 O 0 -4.284 3.090 -0.370 0.00 0.00 O+0<br />
ATOM 2 C 0 -4.565 2.093 0.267 0.00 0.00 C+0<br />
ATOM 3 H 0 -5.014 2.185 1.244 0.00 0.00 H+0<br />
ATOM 4 C 0 -4.301 0.826 -0.264 0.00 0.00 C+0<br />
ATOM 5 H 0 -3.848 0.734 -1.240 0.00 0.00 H+0<br />
ATOM 6 C 0 -4.620 -0.304 0.458 0.00 0.00 C+0<br />
ATOM 7 C 0 -5.252 -0.175 1.820 0.00 0.00 C+0<br />
ATOM 8 H 0 -5.510 -1.165 2.196 0.00 0.00 H+0<br />
ATOM 9 H 0 -4.549 0.302 2.503 0.00 0.00 H+0<br />
ATOM 10 H 0 -6.155 0.431 1.745 0.00 0.00 H+0<br />
ATOM 11 C 0 -4.356 -1.571 -0.074 0.00 0.00 C+0<br />
ATOM 12 H 0 -5.156 -2.288 -0.184 0.00 0.00 H+0<br />
ATOM 13 C 0 -3.075 -1.905 -0.455 0.00 0.00 C+0<br />
ATOM 14 H 0 -2.888 -2.841 -0.961 0.00 0.00 H+0<br />
ATOM 15 C 0 -2.013 -1.030 -0.187 0.00 0.00 C+0<br />
ATOM 16 H 0 -2.209 -0.062 0.250 0.00 0.00 H+0<br />
ATOM 17 C 0 -0.732 -1.401 -0.480 0.00 0.00 C+0<br />
ATOM 18 C 0 -0.460 -2.751 -1.091 0.00 0.00 C+0<br />
ATOM 19 H 0 0.617 -2.905 -1.166 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.895 -3.529 -0.463 0.00 0.00 H+0<br />
ATOM 21 H 0 -0.903 -2.796 -2.086 0.00 0.00 H+0<br />
ATOM 22 C 0 0.332 -0.523 -0.212 0.00 0.00 C+0<br />
ATOM 23 H 0 0.148 0.407 0.306 0.00 0.00 H+0<br />
ATOM 24 C 0 1.593 -0.845 -0.603 0.00 0.00 C+0<br />
ATOM 25 H 0 1.769 -1.745 -1.174 0.00 0.00 H+0<br />
ATOM 26 C 0 2.679 0.001 -0.262 0.00 0.00 C+0<br />
ATOM 27 C 0 2.629 1.266 -0.646 0.00 0.00 C+0<br />
ATOM 28 C 0 1.416 1.729 -1.413 0.00 0.00 C+0<br />
ATOM 29 H 0 0.676 2.124 -0.718 0.00 0.00 H+0<br />
ATOM 30 H 0 1.708 2.509 -2.116 0.00 0.00 H+0<br />
ATOM 31 H 0 0.989 0.888 -1.959 0.00 0.00 H+0<br />
ATOM 32 C 0 3.711 2.266 -0.361 0.00 0.00 C+0<br />
ATOM 33 H 0 4.301 2.427 -1.263 0.00 0.00 H+0<br />
ATOM 34 H 0 3.259 3.209 -0.052 0.00 0.00 H+0<br />
ATOM 35 C 0 4.621 1.753 0.756 0.00 0.00 C+0<br />
ATOM 36 H 0 4.080 1.760 1.702 0.00 0.00 H+0<br />
ATOM 37 H 0 5.501 2.391 0.833 0.00 0.00 H+0<br />
ATOM 38 C 0 5.048 0.319 0.417 0.00 0.00 C+0<br />
ATOM 39 H 0 5.449 0.286 -0.595 0.00 0.00 H+0<br />
ATOM 40 H 0 5.809 -0.013 1.124 0.00 0.00 H+0<br />
ATOM 41 C 0 3.817 -0.587 0.519 0.00 0.00 C+0<br />
ATOM 42 C 0 3.414 -0.733 1.988 0.00 0.00 C+0<br />
ATOM 43 H 0 3.178 0.249 2.399 0.00 0.00 H+0<br />
ATOM 44 H 0 2.538 -1.377 2.062 0.00 0.00 H+0<br />
ATOM 45 H 0 4.238 -1.173 2.549 0.00 0.00 H+0<br />
ATOM 46 C 0 4.155 -1.967 -0.050 0.00 0.00 C+0<br />
ATOM 47 H 0 4.922 -2.436 0.566 0.00 0.00 H+0<br />
ATOM 48 H 0 3.260 -2.589 -0.051 0.00 0.00 H+0<br />
ATOM 49 H 0 4.524 -1.859 -1.070 0.00 0.00 H+0<br />
CONECT 1 2 0 0 0 NONE 54<br />
CONECT 2 1 3 4 0 NONE 55<br />
CONECT 4 2 5 6 0 NONE 56<br />
CONECT 6 4 7 11 0 NONE 57<br />
CONECT 7 6 8 9 10 NONE 58<br />
CONECT 11 6 12 13 0 NONE 59<br />
CONECT 13 11 14 15 0 NONE 60<br />
CONECT 15 13 16 17 0 NONE 61<br />
CONECT 17 15 18 22 0 NONE 62<br />
CONECT 18 17 19 20 21 NONE 63<br />
CONECT 22 17 23 24 0 NONE 64<br />
CONECT 24 22 25 26 0 NONE 65<br />
CONECT 26 24 41 27 0 NONE 66<br />
CONECT 27 26 28 32 0 NONE 67<br />
CONECT 28 27 29 30 31 NONE 68<br />
CONECT 32 27 33 34 35 NONE 69<br />
CONECT 35 32 36 37 38 NONE 70<br />
CONECT 38 35 39 40 41 NONE 71<br />
CONECT 41 38 26 42 46 NONE 72<br />
CONECT 42 41 43 44 45 NONE 73<br />
CONECT 46 41 47 48 49 NONE 74<br />
END NONE 75<br />
NONE 70<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|}<br />
<br />
== Properties of Cis-Retinal and Trans-Retinal ==<br />
<br />
{| class="toccolours" border="1" style="fix : right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" colspan="1" bgcolor="lt blue"|<br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Cis-Retinal''' <br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Trans-Retinal''' <br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''General properties''' <br />
|-<br />
| Chemical name<br />
| align="center"|(11Z)-retinal<br />
| align="center"|...<br />
|-<br />
| Chemical formula<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
|-<br />
| Molecular mass<br />
| align="center"|284 g/mol<br />
| align="center"|284 g/mol<br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''Physical properties'''<br />
|-<br />
| Melting point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Boiling point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Appearance<br />
| align="center"|...<br />
| align="center"|...<br />
|-<br />
| align="center" colspan="3" bgcolor="white" |'''Miscelleneous'''<br />
|-<br />
| SMILES<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C\C(C)=C\C=O)<br />
=C(C)CCC1<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C/C(C)=C/C=O)<br />
=C(C)CCC1<br />
|-<br />
|}<br />
<br />
==Structure of all-trans retinal==<br />
'''2D Structure'''<br />
<br />
[[Image:AllTransRetinal.gif]]<br />
<br />
<br />
<br />
[http://www.ch.ic.ac.uk/wiki/index.php/Image:Trans-retinal.cdx ChemDraw 3D structure]<br />
<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>400</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY BOKSEZ<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 14.761 8.292 15.210 90.00 102.40 90.00 P 21/n 4<br />
ATOM 1 O1 UNK 0 1 8.800 1.137 3.735 1.00 0.00<br />
ATOM 2 O2 UNK 0 1 -3.642 0.109 -1.855 1.00 0.00<br />
ATOM 3 C1 UNK 0 1 7.236 4.986 3.316 1.00 0.00<br />
ATOM 4 C2 UNK 0 1 7.808 4.433 4.641 1.00 0.00<br />
ATOM 5 C3 UNK 0 1 8.881 3.407 4.434 1.00 0.00<br />
ATOM 6 C4 UNK 0 1 8.402 2.292 3.586 1.00 0.00<br />
ATOM 7 C5 UNK 0 1 7.434 2.593 2.496 1.00 0.00<br />
ATOM 8 C6 UNK 0 1 6.851 3.816 2.410 1.00 0.00<br />
ATOM 9 C7 UNK 0 1 5.849 4.111 1.365 1.00 0.00<br />
ATOM 10 C8 UNK 0 1 4.735 3.412 1.188 1.00 0.00<br />
ATOM 11 C9 UNK 0 1 3.695 3.741 0.202 1.00 0.00<br />
ATOM 12 C10 UNK 0 1 2.601 2.943 0.227 1.00 0.00<br />
ATOM 13 C11 UNK 0 1 1.409 3.020 -0.654 1.00 0.00<br />
ATOM 14 C12 UNK 0 1 0.394 2.212 -0.535 1.00 0.00<br />
ATOM 15 C13 UNK 0 1 -0.769 2.174 -1.450 1.00 0.00<br />
ATOM 16 C14 UNK 0 1 -1.684 1.256 -1.236 1.00 0.00<br />
ATOM 17 C15 UNK 0 1 -2.881 0.999 -2.043 1.00 0.00<br />
ATOM 18 C16 UNK 0 1 7.167 1.427 1.567 1.00 0.00<br />
ATOM 19 C17 UNK 0 1 5.974 5.755 3.760 1.00 0.00<br />
ATOM 20 C18 UNK 0 1 8.204 5.906 2.607 1.00 0.00<br />
ATOM 21 C19 UNK 0 1 3.919 4.853 -0.787 1.00 0.00<br />
ATOM 22 C20 UNK 0 1 -0.796 3.178 -2.557 1.00 0.00<br />
ATOM 23 H1 UNK 0 1 6.939 4.113 5.229 1.00 0.00<br />
ATOM 24 H2 UNK 0 1 8.383 5.232 5.110 1.00 0.00<br />
ATOM 25 H3 UNK 0 1 9.085 3.458 5.274 1.00 0.00<br />
ATOM 26 H4 UNK 0 1 9.452 3.930 3.803 1.00 0.00<br />
ATOM 27 H5 UNK 0 1 6.133 4.784 0.772 1.00 0.00<br />
ATOM 28 H6 UNK 0 1 4.476 2.728 1.797 1.00 0.00<br />
ATOM 29 H7 UNK 0 1 2.453 2.222 0.995 1.00 0.00<br />
ATOM 30 H8 UNK 0 1 1.583 3.856 -1.292 1.00 0.00<br />
ATOM 31 H9 UNK 0 1 0.154 1.750 0.238 1.00 0.00<br />
ATOM 32 H10 UNK 0 1 -1.746 0.871 -0.520 1.00 0.00<br />
ATOM 33 H11 UNK 0 1 -2.722 1.857 -2.659 1.00 0.00<br />
ATOM 34 H12 UNK 0 1 5.584 6.194 3.134 1.00 0.00<br />
ATOM 35 H13 UNK 0 1 5.249 5.174 4.323 1.00 0.00<br />
ATOM 36 H14 UNK 0 1 6.345 6.509 4.442 1.00 0.00<br />
ATOM 37 H15 UNK 0 1 7.632 6.136 2.080 1.00 0.00<br />
ATOM 38 H16 UNK 0 1 9.036 5.224 2.674 1.00 0.00<br />
ATOM 39 H17 UNK 0 1 8.192 0.796 1.411 1.00 0.00<br />
ATOM 40 H18 UNK 0 1 6.845 1.683 0.891 1.00 0.00<br />
ATOM 41 H19 UNK 0 1 6.601 0.730 1.664 1.00 0.00<br />
ATOM 42 H20 UNK 0 1 3.287 5.000 -1.055 1.00 0.00<br />
ATOM 43 H21 UNK 0 1 3.641 5.431 -0.312 1.00 0.00<br />
ATOM 44 H22 UNK 0 1 4.744 4.677 -1.233 1.00 0.00<br />
ATOM 45 H23 UNK 0 1 -1.169 2.952 -3.075 1.00 0.00<br />
ATOM 46 H24 UNK 0 1 -1.270 3.988 -2.080 1.00 0.00<br />
ATOM 47 H25 UNK 0 1 -0.054 3.018 -3.313 1.00 0.00<br />
CONECT 1 6<br />
CONECT 2 17<br />
CONECT 3 4 8 19 20<br />
CONECT 4 3 5 23 24<br />
CONECT 5 4 6 25 26<br />
CONECT 6 1 5 7<br />
CONECT 7 6 8 18<br />
CONECT 8 3 7 9<br />
CONECT 9 8 10 27<br />
CONECT 10 9 11 28<br />
CONECT 11 10 12 21<br />
CONECT 12 11 13 29<br />
CONECT 13 12 14 30<br />
CONECT 14 13 15 31<br />
CONECT 15 14 16 22<br />
CONECT 16 15 17 32<br />
CONECT 17 2 16 33<br />
CONECT 18 7 39 40 41<br />
CONECT 19 3 34 35 36<br />
CONECT 20 3 37 38<br />
CONECT 21 11 42 43 44<br />
CONECT 22 15 45 46 47<br />
CONECT 23 4<br />
CONECT 24 4<br />
CONECT 25 5<br />
CONECT 26 5<br />
CONECT 27 9<br />
CONECT 28 10<br />
CONECT 29 12<br />
CONECT 30 13<br />
CONECT 31 14<br />
CONECT 32 16<br />
CONECT 33 17<br />
CONECT 34 19<br />
CONECT 35 19<br />
CONECT 36 19<br />
CONECT 37 20<br />
CONECT 38 20<br />
CONECT 39 18<br />
CONECT 40 18<br />
CONECT 41 18<br />
CONECT 42 21<br />
CONECT 43 21<br />
CONECT 44 21<br />
CONECT 45 22<br />
CONECT 46 22<br />
CONECT 47 22<br />
MASTER 0 0 0 0 0 0 0 0 47 0 47 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
==The role of retinal in the vision process==<br />
<br />
The molecule that takes part in the vision process is rhodopsin which consists of 11-cis retinal and protein opsin. Retinal is a Vitamin A derivative. When there is no light present the 11-cis retinal has a bent configuration and is attached to the retinal molecule in a stable arrangement. When light strikes the retina, the retinal molecule absorbs a photon into one of the pi-bonds between the 11th and 12th carbon atoms, hence the 11 cis retinal is transfformed into the all trans retinal.<br />
<br />
[[Image:RetinalConversion.png]]<br />
<br>Compound A 3D Picture<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>white</color><br />
<script>zoom 100; cpk ;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY CRETAL01<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 13.180 7.499 17.803 90.00 95.66 90.00 P 21/n 4<br />
ATOM 1 C1 UNK 0 1 3.279 5.402 15.975 1.00 0.00<br />
ATOM 2 C2 UNK 0 1 4.046 6.337 15.055 1.00 0.00<br />
ATOM 3 C3 UNK 0 1 3.501 7.731 15.036 1.00 0.00<br />
ATOM 4 C4 UNK 0 1 2.048 7.716 14.547 1.00 0.00<br />
ATOM 5 C5 UNK 0 1 1.242 6.570 15.071 1.00 0.00<br />
ATOM 6 C6 UNK 0 1 1.742 5.525 15.720 1.00 0.00<br />
ATOM 7 C7 UNK 0 1 0.960 4.412 16.249 1.00 0.00<br />
ATOM 8 C8 UNK 0 1 -0.096 3.785 15.688 1.00 0.00<br />
ATOM 9 C9 UNK 0 1 -0.891 2.748 16.260 1.00 0.00<br />
ATOM 10 C10 UNK 0 1 -2.039 2.359 15.656 1.00 0.00<br />
ATOM 11 C11 UNK 0 1 -2.995 1.432 16.171 1.00 0.00<br />
ATOM 12 C12 UNK 0 1 -4.118 0.952 15.603 1.00 0.00<br />
ATOM 13 C13 UNK 0 1 -4.579 1.155 14.210 1.00 0.00<br />
ATOM 14 C14 UNK 0 1 -3.772 1.162 13.168 1.00 0.00<br />
ATOM 15 C15 UNK 0 1 -4.144 1.290 11.748 1.00 0.00<br />
ATOM 16 O1 UNK 0 1 -3.417 1.200 10.832 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 -0.251 6.757 14.825 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 3.537 5.722 17.465 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 3.755 3.989 15.704 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 -0.446 2.130 17.555 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 -6.097 1.275 14.125 1.00 0.00<br />
ATOM 22 H1 UNK 0 1 4.961 6.299 15.236 1.00 0.00<br />
ATOM 23 H2 UNK 0 1 4.033 6.074 13.960 1.00 0.00<br />
ATOM 24 H3 UNK 0 1 3.361 8.099 16.086 1.00 0.00<br />
ATOM 25 H4 UNK 0 1 4.112 8.346 14.368 1.00 0.00<br />
ATOM 26 H5 UNK 0 1 1.613 8.609 14.846 1.00 0.00<br />
ATOM 27 H6 UNK 0 1 2.096 8.271 13.429 1.00 0.00<br />
ATOM 28 H7 UNK 0 1 1.167 4.027 17.220 1.00 0.00<br />
ATOM 29 H8 UNK 0 1 -0.283 4.132 14.828 1.00 0.00<br />
ATOM 30 H9 UNK 0 1 -2.166 2.700 14.811 1.00 0.00<br />
ATOM 31 H10 UNK 0 1 -2.959 1.140 17.220 1.00 0.00<br />
ATOM 32 H11 UNK 0 1 -4.766 0.337 16.175 1.00 0.00<br />
ATOM 33 H12 UNK 0 1 -2.863 1.012 13.199 1.00 0.00<br />
ATOM 34 H13 UNK 0 1 -5.051 1.500 11.604 1.00 0.00<br />
ATOM 35 H14 UNK 0 1 -0.500 7.641 14.882 1.00 0.00<br />
ATOM 36 H15 UNK 0 1 -0.354 6.404 13.677 1.00 0.00<br />
ATOM 37 H16 UNK 0 1 -0.828 6.374 15.537 1.00 0.00<br />
ATOM 38 H17 UNK 0 1 4.443 5.482 17.539 1.00 0.00<br />
ATOM 39 H18 UNK 0 1 3.171 6.749 17.876 1.00 0.00<br />
ATOM 40 H19 UNK 0 1 2.971 5.092 18.159 1.00 0.00<br />
ATOM 41 H20 UNK 0 1 3.359 3.330 16.246 1.00 0.00<br />
ATOM 42 H21 UNK 0 1 3.564 3.712 14.704 1.00 0.00<br />
ATOM 43 H22 UNK 0 1 4.832 3.967 15.608 1.00 0.00<br />
ATOM 44 H23 UNK 0 1 0.526 2.025 17.433 1.00 0.00<br />
ATOM 45 H24 UNK 0 1 -0.489 2.700 18.230 1.00 0.00<br />
ATOM 46 H25 UNK 0 1 -1.006 1.387 18.000 1.00 0.00<br />
ATOM 47 H26 UNK 0 1 -6.646 0.300 14.793 1.00 0.00<br />
ATOM 48 H27 UNK 0 1 -6.440 2.100 14.580 1.00 0.00<br />
ATOM 49 H28 UNK 0 1 -6.271 1.320 13.269 1.00 0.00<br />
CONECT 1 2 6 18 19<br />
CONECT 2 1 3 22 23<br />
CONECT 3 2 4 24 25<br />
CONECT 4 3 5 26 27<br />
CONECT 5 4 6 17<br />
CONECT 6 1 5 7<br />
CONECT 7 6 8 28<br />
CONECT 8 7 9 29<br />
CONECT 9 8 10 20<br />
CONECT 10 9 11 30<br />
CONECT 11 10 12 31<br />
CONECT 12 11 13 32<br />
CONECT 13 12 14 21<br />
CONECT 14 13 15 33<br />
CONECT 15 14 16 34<br />
CONECT 16 15<br />
CONECT 17 5 35 36 37<br />
CONECT 18 1 38 39 40<br />
CONECT 19 1 41 42 43<br />
CONECT 20 9 44 45 46<br />
CONECT 21 13 47 48 49<br />
CONECT 22 2<br />
CONECT 23 2<br />
CONECT 24 3<br />
CONECT 25 3<br />
CONECT 26 4<br />
CONECT 27 4<br />
CONECT 28 7<br />
CONECT 29 8<br />
CONECT 30 10<br />
CONECT 31 11<br />
CONECT 32 12<br />
CONECT 33 14<br />
CONECT 34 15<br />
CONECT 35 17<br />
CONECT 36 17<br />
CONECT 37 17<br />
CONECT 38 18<br />
CONECT 39 18<br />
CONECT 40 18<br />
CONECT 41 19<br />
CONECT 42 19<br />
CONECT 43 19<br />
CONECT 44 20<br />
CONECT 45 20<br />
CONECT 46 20<br />
CONECT 47 21<br />
CONECT 48 21<br />
CONECT 49 21<br />
MASTER 0 0 0 0 0 0 0 0 49 0 49 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
Compound B 3D picture<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>white</color><br />
<script>zoom 100; cpk ;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY TRETAL03<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 14.956 8.277 15.291 90.00 104.92 90.00 P 21/n 4<br />
ATOM 1 O1 UNK 0 1 9.309 3.852 9.139 1.00 0.00<br />
ATOM 2 C1 UNK 0 1 -1.723 -0.739 4.047 1.00 0.00<br />
ATOM 3 C2 UNK 0 1 -0.452 -1.316 3.444 1.00 0.00<br />
ATOM 4 C3 UNK 0 1 -2.519 -1.832 4.761 1.00 0.00<br />
ATOM 5 C4 UNK 0 1 -2.460 -0.197 2.791 1.00 0.00<br />
ATOM 6 C5 UNK 0 1 -3.484 0.764 3.073 1.00 0.00<br />
ATOM 7 C6 UNK 0 1 -3.039 1.904 3.908 1.00 0.00<br />
ATOM 8 C7 UNK 0 1 -2.002 1.579 4.954 1.00 0.00<br />
ATOM 9 C8 UNK 0 1 -1.767 2.692 5.929 1.00 0.00<br />
ATOM 10 C9 UNK 0 1 -1.402 0.397 5.000 1.00 0.00<br />
ATOM 11 C10 UNK 0 1 -0.360 0.092 6.017 1.00 0.00<br />
ATOM 12 C11 UNK 0 1 0.764 0.756 6.175 1.00 0.00<br />
ATOM 13 C12 UNK 0 1 1.826 0.493 7.151 1.00 0.00<br />
ATOM 14 C13 UNK 0 1 1.604 -0.603 8.138 1.00 0.00<br />
ATOM 15 C14 UNK 0 1 2.930 1.234 7.109 1.00 0.00<br />
ATOM 16 C15 UNK 0 1 4.081 1.142 7.980 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 5.145 1.932 7.893 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 6.289 1.962 8.796 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 6.288 1.002 9.940 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 7.263 2.851 8.564 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 8.452 3.036 9.396 1.00 0.00<br />
CONECT 1 21<br />
CONECT 2 3 4 5 10<br />
CONECT 3 2<br />
CONECT 4 2<br />
CONECT 5 2 6<br />
CONECT 6 5 7<br />
CONECT 7 6 8<br />
CONECT 8 7 9 10<br />
CONECT 9 8<br />
CONECT 10 2 8 11<br />
CONECT 11 10 12<br />
CONECT 12 11 13<br />
CONECT 13 12 14 15<br />
CONECT 14 13<br />
CONECT 15 13 16<br />
CONECT 16 15 17<br />
CONECT 17 16 18<br />
CONECT 18 17 19 20<br />
CONECT 19 18<br />
CONECT 20 18 21<br />
CONECT 21 1 20<br />
MASTER 0 0 0 0 0 0 0 0 21 0 21 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
==Synthesis of Rhodopsin==<br />
[[Image:Synthesis_of_rhodopsin.gif]]<br />
<br />
==Effects of Bunazosin on ocular circulation and retinal neuronal damage==<br />
<br />
By applying bunazosin hydrochloride into a healthy humans, it increases the blood velocity in the optic nerve head(ONH),retina and choroid, without changing either heart rate and blood pressure dramaticallt. This drug was also applied to rabbits and rats, giving positive results. These shows that bunazosin hydrochloride have improvement effect both in the ocular circulation and a direct neuroprotective effct. Therefore, it may be useful to use bunazosin hydrochloride as a therapeutic drug against retinal diseases which is associated with the ocular circulation.<br />
<br />
== References ==<br />
<br />
*Beilstein Data: Copyright (c) 1988-2006, Beilstein institut zur Foerderung der Chemischen Wissenschaften licensed to Beilstein GmBH and MDL information systems GmbH<br />
<br />
*1.Chang, Raymond (1998). Chemistry, 6th Ed.. New York: McGraw Hill. ISBN 0-07-115221-0. <br />
*2. Feynman, Richard (1985). QED - The Strange Theory of Light and Matter. Princeton, New Jersey: Princeton University Press. ISBN 0691024170.<br />
*3.Hara, Hideaki / Ichikawa, Masaki / Oku, Hidehiro / Shimazawa, Masamitsu / Araie, Makoto, Cardiovascular drug reviews, Apr 2005</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Retinal&diff=4898
It:Retinal
2006-11-06T12:08:40Z
<p>Qlw05: /* Structure of all-trans retinal */</p>
<hr />
<div>__toc__<br />
<br />
'''Retinal''', also known as retinaldehyde or retinene<sub>1</sub> is the most important molecule associated with vision. Retinal changes structure when it is exposed to light, essentially transferring the energy from the light it absorbs to an electrical impulse in the retina of the eye, which is then passed along the optic nerve to the central nervous system to be processed. All vision systems operate in this manner, so Retinal is resposible for all vision. Retinal is a retinine molecule that exists as two different isomers - 11-cis retinal and all-trans retinal.<br />
<br />
== Structure of Cis-Retinal ==<br />
<br />
{| class="toccolours" border="0" style="fix: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" bgcolor="lt blue"|'''2D Structure'''<br />
| align="center" bgcolor="lt blue"|'''3D Structure'''<br />
|-<br />
| [[image:Cis-RetinalSo.gif]]<br />
|<jmol><br />
<jmolApplet><br />
<size>350</size><br />
<color>white</color><br />
<script>zoom 100; bns on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
HEADER NONAME 23-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 23-Oct-06 0 NONE 4<br />
ATOM 1 O 0 -4.284 3.090 -0.370 0.00 0.00 O+0<br />
ATOM 2 C 0 -4.565 2.093 0.267 0.00 0.00 C+0<br />
ATOM 3 H 0 -5.014 2.185 1.244 0.00 0.00 H+0<br />
ATOM 4 C 0 -4.301 0.826 -0.264 0.00 0.00 C+0<br />
ATOM 5 H 0 -3.848 0.734 -1.240 0.00 0.00 H+0<br />
ATOM 6 C 0 -4.620 -0.304 0.458 0.00 0.00 C+0<br />
ATOM 7 C 0 -5.252 -0.175 1.820 0.00 0.00 C+0<br />
ATOM 8 H 0 -5.510 -1.165 2.196 0.00 0.00 H+0<br />
ATOM 9 H 0 -4.549 0.302 2.503 0.00 0.00 H+0<br />
ATOM 10 H 0 -6.155 0.431 1.745 0.00 0.00 H+0<br />
ATOM 11 C 0 -4.356 -1.571 -0.074 0.00 0.00 C+0<br />
ATOM 12 H 0 -5.156 -2.288 -0.184 0.00 0.00 H+0<br />
ATOM 13 C 0 -3.075 -1.905 -0.455 0.00 0.00 C+0<br />
ATOM 14 H 0 -2.888 -2.841 -0.961 0.00 0.00 H+0<br />
ATOM 15 C 0 -2.013 -1.030 -0.187 0.00 0.00 C+0<br />
ATOM 16 H 0 -2.209 -0.062 0.250 0.00 0.00 H+0<br />
ATOM 17 C 0 -0.732 -1.401 -0.480 0.00 0.00 C+0<br />
ATOM 18 C 0 -0.460 -2.751 -1.091 0.00 0.00 C+0<br />
ATOM 19 H 0 0.617 -2.905 -1.166 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.895 -3.529 -0.463 0.00 0.00 H+0<br />
ATOM 21 H 0 -0.903 -2.796 -2.086 0.00 0.00 H+0<br />
ATOM 22 C 0 0.332 -0.523 -0.212 0.00 0.00 C+0<br />
ATOM 23 H 0 0.148 0.407 0.306 0.00 0.00 H+0<br />
ATOM 24 C 0 1.593 -0.845 -0.603 0.00 0.00 C+0<br />
ATOM 25 H 0 1.769 -1.745 -1.174 0.00 0.00 H+0<br />
ATOM 26 C 0 2.679 0.001 -0.262 0.00 0.00 C+0<br />
ATOM 27 C 0 2.629 1.266 -0.646 0.00 0.00 C+0<br />
ATOM 28 C 0 1.416 1.729 -1.413 0.00 0.00 C+0<br />
ATOM 29 H 0 0.676 2.124 -0.718 0.00 0.00 H+0<br />
ATOM 30 H 0 1.708 2.509 -2.116 0.00 0.00 H+0<br />
ATOM 31 H 0 0.989 0.888 -1.959 0.00 0.00 H+0<br />
ATOM 32 C 0 3.711 2.266 -0.361 0.00 0.00 C+0<br />
ATOM 33 H 0 4.301 2.427 -1.263 0.00 0.00 H+0<br />
ATOM 34 H 0 3.259 3.209 -0.052 0.00 0.00 H+0<br />
ATOM 35 C 0 4.621 1.753 0.756 0.00 0.00 C+0<br />
ATOM 36 H 0 4.080 1.760 1.702 0.00 0.00 H+0<br />
ATOM 37 H 0 5.501 2.391 0.833 0.00 0.00 H+0<br />
ATOM 38 C 0 5.048 0.319 0.417 0.00 0.00 C+0<br />
ATOM 39 H 0 5.449 0.286 -0.595 0.00 0.00 H+0<br />
ATOM 40 H 0 5.809 -0.013 1.124 0.00 0.00 H+0<br />
ATOM 41 C 0 3.817 -0.587 0.519 0.00 0.00 C+0<br />
ATOM 42 C 0 3.414 -0.733 1.988 0.00 0.00 C+0<br />
ATOM 43 H 0 3.178 0.249 2.399 0.00 0.00 H+0<br />
ATOM 44 H 0 2.538 -1.377 2.062 0.00 0.00 H+0<br />
ATOM 45 H 0 4.238 -1.173 2.549 0.00 0.00 H+0<br />
ATOM 46 C 0 4.155 -1.967 -0.050 0.00 0.00 C+0<br />
ATOM 47 H 0 4.922 -2.436 0.566 0.00 0.00 H+0<br />
ATOM 48 H 0 3.260 -2.589 -0.051 0.00 0.00 H+0<br />
ATOM 49 H 0 4.524 -1.859 -1.070 0.00 0.00 H+0<br />
CONECT 1 2 0 0 0 NONE 54<br />
CONECT 2 1 3 4 0 NONE 55<br />
CONECT 4 2 5 6 0 NONE 56<br />
CONECT 6 4 7 11 0 NONE 57<br />
CONECT 7 6 8 9 10 NONE 58<br />
CONECT 11 6 12 13 0 NONE 59<br />
CONECT 13 11 14 15 0 NONE 60<br />
CONECT 15 13 16 17 0 NONE 61<br />
CONECT 17 15 18 22 0 NONE 62<br />
CONECT 18 17 19 20 21 NONE 63<br />
CONECT 22 17 23 24 0 NONE 64<br />
CONECT 24 22 25 26 0 NONE 65<br />
CONECT 26 24 41 27 0 NONE 66<br />
CONECT 27 26 28 32 0 NONE 67<br />
CONECT 28 27 29 30 31 NONE 68<br />
CONECT 32 27 33 34 35 NONE 69<br />
CONECT 35 32 36 37 38 NONE 70<br />
CONECT 38 35 39 40 41 NONE 71<br />
CONECT 41 38 26 42 46 NONE 72<br />
CONECT 42 41 43 44 45 NONE 73<br />
CONECT 46 41 47 48 49 NONE 74<br />
END NONE 75<br />
NONE 70<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|}<br />
<br />
== Properties of Cis-Retinal and Trans-Retinal ==<br />
<br />
{| class="toccolours" border="1" style="fix : right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" colspan="1" bgcolor="lt blue"|<br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Cis-Retinal''' <br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Trans-Retinal''' <br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''General properties''' <br />
|-<br />
| Chemical name<br />
| align="center"|(11Z)-retinal<br />
| align="center"|...<br />
|-<br />
| Chemical formula<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
|-<br />
| Molecular mass<br />
| align="center"|284 g/mol<br />
| align="center"|284 g/mol<br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''Physical properties'''<br />
|-<br />
| Melting point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Boiling point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Appearance<br />
| align="center"|...<br />
| align="center"|...<br />
|-<br />
| align="center" colspan="3" bgcolor="white" |'''Miscelleneous'''<br />
|-<br />
| SMILES<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C\C(C)=C\C=O)<br />
=C(C)CCC1<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C/C(C)=C/C=O)<br />
=C(C)CCC1<br />
|-<br />
|}<br />
<br />
==Structure of all-trans retinal==<br />
'''2D Structure'''<br />
<br />
[[Image:AllTransRetinal.gif]]<br />
<br />
<br />
<br />
[http://www.ch.ic.ac.uk/wiki/index.php/Image:Trans-retinal.cdx 3D structure]<br />
<br />
==The role of retinal in the vision process==<br />
<br />
The molecule that takes part in the vision process is rhodopsin which consists of 11-cis retinal and protein opsin. Retinal is a Vitamin A derivative. When there is no light present the 11-cis retinal has a bent configuration and is attached to the retinal molecule in a stable arrangement. When light strikes the retina, the retinal molecule absorbs a photon into one of the pi-bonds between the 11th and 12th carbon atoms, hence the 11 cis retinal is transfformed into the all trans retinal.<br />
<br />
[[Image:RetinalConversion.png]]<br />
<br>Compound A 3D Picture<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>white</color><br />
<script>zoom 100; cpk ;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY CRETAL01<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 13.180 7.499 17.803 90.00 95.66 90.00 P 21/n 4<br />
ATOM 1 C1 UNK 0 1 3.279 5.402 15.975 1.00 0.00<br />
ATOM 2 C2 UNK 0 1 4.046 6.337 15.055 1.00 0.00<br />
ATOM 3 C3 UNK 0 1 3.501 7.731 15.036 1.00 0.00<br />
ATOM 4 C4 UNK 0 1 2.048 7.716 14.547 1.00 0.00<br />
ATOM 5 C5 UNK 0 1 1.242 6.570 15.071 1.00 0.00<br />
ATOM 6 C6 UNK 0 1 1.742 5.525 15.720 1.00 0.00<br />
ATOM 7 C7 UNK 0 1 0.960 4.412 16.249 1.00 0.00<br />
ATOM 8 C8 UNK 0 1 -0.096 3.785 15.688 1.00 0.00<br />
ATOM 9 C9 UNK 0 1 -0.891 2.748 16.260 1.00 0.00<br />
ATOM 10 C10 UNK 0 1 -2.039 2.359 15.656 1.00 0.00<br />
ATOM 11 C11 UNK 0 1 -2.995 1.432 16.171 1.00 0.00<br />
ATOM 12 C12 UNK 0 1 -4.118 0.952 15.603 1.00 0.00<br />
ATOM 13 C13 UNK 0 1 -4.579 1.155 14.210 1.00 0.00<br />
ATOM 14 C14 UNK 0 1 -3.772 1.162 13.168 1.00 0.00<br />
ATOM 15 C15 UNK 0 1 -4.144 1.290 11.748 1.00 0.00<br />
ATOM 16 O1 UNK 0 1 -3.417 1.200 10.832 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 -0.251 6.757 14.825 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 3.537 5.722 17.465 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 3.755 3.989 15.704 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 -0.446 2.130 17.555 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 -6.097 1.275 14.125 1.00 0.00<br />
ATOM 22 H1 UNK 0 1 4.961 6.299 15.236 1.00 0.00<br />
ATOM 23 H2 UNK 0 1 4.033 6.074 13.960 1.00 0.00<br />
ATOM 24 H3 UNK 0 1 3.361 8.099 16.086 1.00 0.00<br />
ATOM 25 H4 UNK 0 1 4.112 8.346 14.368 1.00 0.00<br />
ATOM 26 H5 UNK 0 1 1.613 8.609 14.846 1.00 0.00<br />
ATOM 27 H6 UNK 0 1 2.096 8.271 13.429 1.00 0.00<br />
ATOM 28 H7 UNK 0 1 1.167 4.027 17.220 1.00 0.00<br />
ATOM 29 H8 UNK 0 1 -0.283 4.132 14.828 1.00 0.00<br />
ATOM 30 H9 UNK 0 1 -2.166 2.700 14.811 1.00 0.00<br />
ATOM 31 H10 UNK 0 1 -2.959 1.140 17.220 1.00 0.00<br />
ATOM 32 H11 UNK 0 1 -4.766 0.337 16.175 1.00 0.00<br />
ATOM 33 H12 UNK 0 1 -2.863 1.012 13.199 1.00 0.00<br />
ATOM 34 H13 UNK 0 1 -5.051 1.500 11.604 1.00 0.00<br />
ATOM 35 H14 UNK 0 1 -0.500 7.641 14.882 1.00 0.00<br />
ATOM 36 H15 UNK 0 1 -0.354 6.404 13.677 1.00 0.00<br />
ATOM 37 H16 UNK 0 1 -0.828 6.374 15.537 1.00 0.00<br />
ATOM 38 H17 UNK 0 1 4.443 5.482 17.539 1.00 0.00<br />
ATOM 39 H18 UNK 0 1 3.171 6.749 17.876 1.00 0.00<br />
ATOM 40 H19 UNK 0 1 2.971 5.092 18.159 1.00 0.00<br />
ATOM 41 H20 UNK 0 1 3.359 3.330 16.246 1.00 0.00<br />
ATOM 42 H21 UNK 0 1 3.564 3.712 14.704 1.00 0.00<br />
ATOM 43 H22 UNK 0 1 4.832 3.967 15.608 1.00 0.00<br />
ATOM 44 H23 UNK 0 1 0.526 2.025 17.433 1.00 0.00<br />
ATOM 45 H24 UNK 0 1 -0.489 2.700 18.230 1.00 0.00<br />
ATOM 46 H25 UNK 0 1 -1.006 1.387 18.000 1.00 0.00<br />
ATOM 47 H26 UNK 0 1 -6.646 0.300 14.793 1.00 0.00<br />
ATOM 48 H27 UNK 0 1 -6.440 2.100 14.580 1.00 0.00<br />
ATOM 49 H28 UNK 0 1 -6.271 1.320 13.269 1.00 0.00<br />
CONECT 1 2 6 18 19<br />
CONECT 2 1 3 22 23<br />
CONECT 3 2 4 24 25<br />
CONECT 4 3 5 26 27<br />
CONECT 5 4 6 17<br />
CONECT 6 1 5 7<br />
CONECT 7 6 8 28<br />
CONECT 8 7 9 29<br />
CONECT 9 8 10 20<br />
CONECT 10 9 11 30<br />
CONECT 11 10 12 31<br />
CONECT 12 11 13 32<br />
CONECT 13 12 14 21<br />
CONECT 14 13 15 33<br />
CONECT 15 14 16 34<br />
CONECT 16 15<br />
CONECT 17 5 35 36 37<br />
CONECT 18 1 38 39 40<br />
CONECT 19 1 41 42 43<br />
CONECT 20 9 44 45 46<br />
CONECT 21 13 47 48 49<br />
CONECT 22 2<br />
CONECT 23 2<br />
CONECT 24 3<br />
CONECT 25 3<br />
CONECT 26 4<br />
CONECT 27 4<br />
CONECT 28 7<br />
CONECT 29 8<br />
CONECT 30 10<br />
CONECT 31 11<br />
CONECT 32 12<br />
CONECT 33 14<br />
CONECT 34 15<br />
CONECT 35 17<br />
CONECT 36 17<br />
CONECT 37 17<br />
CONECT 38 18<br />
CONECT 39 18<br />
CONECT 40 18<br />
CONECT 41 19<br />
CONECT 42 19<br />
CONECT 43 19<br />
CONECT 44 20<br />
CONECT 45 20<br />
CONECT 46 20<br />
CONECT 47 21<br />
CONECT 48 21<br />
CONECT 49 21<br />
MASTER 0 0 0 0 0 0 0 0 49 0 49 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
Compound B 3D picture<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>white</color><br />
<script>zoom 100; cpk ;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY TRETAL03<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 14.956 8.277 15.291 90.00 104.92 90.00 P 21/n 4<br />
ATOM 1 O1 UNK 0 1 9.309 3.852 9.139 1.00 0.00<br />
ATOM 2 C1 UNK 0 1 -1.723 -0.739 4.047 1.00 0.00<br />
ATOM 3 C2 UNK 0 1 -0.452 -1.316 3.444 1.00 0.00<br />
ATOM 4 C3 UNK 0 1 -2.519 -1.832 4.761 1.00 0.00<br />
ATOM 5 C4 UNK 0 1 -2.460 -0.197 2.791 1.00 0.00<br />
ATOM 6 C5 UNK 0 1 -3.484 0.764 3.073 1.00 0.00<br />
ATOM 7 C6 UNK 0 1 -3.039 1.904 3.908 1.00 0.00<br />
ATOM 8 C7 UNK 0 1 -2.002 1.579 4.954 1.00 0.00<br />
ATOM 9 C8 UNK 0 1 -1.767 2.692 5.929 1.00 0.00<br />
ATOM 10 C9 UNK 0 1 -1.402 0.397 5.000 1.00 0.00<br />
ATOM 11 C10 UNK 0 1 -0.360 0.092 6.017 1.00 0.00<br />
ATOM 12 C11 UNK 0 1 0.764 0.756 6.175 1.00 0.00<br />
ATOM 13 C12 UNK 0 1 1.826 0.493 7.151 1.00 0.00<br />
ATOM 14 C13 UNK 0 1 1.604 -0.603 8.138 1.00 0.00<br />
ATOM 15 C14 UNK 0 1 2.930 1.234 7.109 1.00 0.00<br />
ATOM 16 C15 UNK 0 1 4.081 1.142 7.980 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 5.145 1.932 7.893 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 6.289 1.962 8.796 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 6.288 1.002 9.940 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 7.263 2.851 8.564 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 8.452 3.036 9.396 1.00 0.00<br />
CONECT 1 21<br />
CONECT 2 3 4 5 10<br />
CONECT 3 2<br />
CONECT 4 2<br />
CONECT 5 2 6<br />
CONECT 6 5 7<br />
CONECT 7 6 8<br />
CONECT 8 7 9 10<br />
CONECT 9 8<br />
CONECT 10 2 8 11<br />
CONECT 11 10 12<br />
CONECT 12 11 13<br />
CONECT 13 12 14 15<br />
CONECT 14 13<br />
CONECT 15 13 16<br />
CONECT 16 15 17<br />
CONECT 17 16 18<br />
CONECT 18 17 19 20<br />
CONECT 19 18<br />
CONECT 20 18 21<br />
CONECT 21 1 20<br />
MASTER 0 0 0 0 0 0 0 0 21 0 21 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
==Synthesis of Rhodopsin==<br />
[[Image:Synthesis_of_rhodopsin.gif]]<br />
<br />
==Effects of Bunazosin on ocular circulation and retinal neuronal damage==<br />
<br />
By applying bunazosin hydrochloride into a healthy humans, it increases the blood velocity in the optic nerve head(ONH),retina and choroid, without changing either heart rate and blood pressure dramaticallt. This drug was also applied to rabbits and rats, giving positive results. These shows that bunazosin hydrochloride have improvement effect both in the ocular circulation and a direct neuroprotective effct. Therefore, it may be useful to use bunazosin hydrochloride as a therapeutic drug against retinal diseases which is associated with the ocular circulation.<br />
<br />
== References ==<br />
<br />
*Beilstein Data: Copyright (c) 1988-2006, Beilstein institut zur Foerderung der Chemischen Wissenschaften licensed to Beilstein GmBH and MDL information systems GmbH<br />
<br />
*1.Chang, Raymond (1998). Chemistry, 6th Ed.. New York: McGraw Hill. ISBN 0-07-115221-0. <br />
*2. Feynman, Richard (1985). QED - The Strange Theory of Light and Matter. Princeton, New Jersey: Princeton University Press. ISBN 0691024170.<br />
*3.Hara, Hideaki / Ichikawa, Masaki / Oku, Hidehiro / Shimazawa, Masamitsu / Araie, Makoto, Cardiovascular drug reviews, Apr 2005</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=File:Trans-retinal.cdx&diff=4897
File:Trans-retinal.cdx
2006-11-06T12:06:08Z
<p>Qlw05: </p>
<hr />
<div></div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4620
It:Methoxsalen
2006-10-28T14:56:07Z
<p>Qlw05: /* Uses and Dosage */</p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
The first uses of psoralen-containing plant extracts in photochemotherapy to cure vitiligo recorded date back to 1500B.C. in India and Egypt. The abbreviation of PUVA was first used in 1974 after successful treatment of severe psoriasis using psoranlen (typically 8-methoxypsoralen) and UVA. Methoxsalen is used recently in combination with UVA in the therapy of vitiligo, severe psoriasis, cutaneous T-cell lymphoma, mycosis fungoides, and other forms of photosensitivity.<br />
<br />
<br>There are several forms of treatments: topical, bath, oral and extracorporeal (outside the body) available but by prescription only.<br />
<br />
*'''Topical Solution''':<br><br />
This may be used to cure vitiligo. It is applied to the affected area then waited for it dry for few minutes before second application. The treated area is then exposed to UVA for 2hrs later.<br />
<br />
*'''Bathwater''':<br><br />
It is used for treatments to small areas, such as hands and feet. The area is treated by soaked in a dilute solution of methoxsalen for half an hour and then exposed to UVA immediately.<br />
<br />
*'''Oral preparation''':<br><br />
This is existed as hard and soft gelatine capsules that used to cure mycosis fungoides, vitiligo and posriasis. This may be given twice or three times a week having at least 48 hrs between each treatments.<br />
<br />
*'''Extracorporeal''':<br><br />
The white blood cells is removed from the blood and treated in a process called photophersis--methoxsalen along with UVA to control skin problems which caused by cutaneous T-cell lymphoma which is a cancer of the lymph system. After the therapy, the blood cells are returned to the body.<br />
<br><br />
<br><br />
<br><br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html<br><br />
6)[http://ntp-server.niehs.nih.gov/ntp/roc/eleventh/profiles/s104meth.pdf 11th ROC: Methoxsalen with Ultraviolet A Therapy (PUVA)]</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4619
It:Methoxsalen
2006-10-28T14:54:58Z
<p>Qlw05: /* Side Effects */</p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
The first uses of psoralen-containing plant extracts in photochemotherapy to cure vitiligo recorded date back to 1500B.C. in India and Egypt. The abbreviation of PUVA was first used in 1974 after successful treatment of severe psoriasis using psoranlen (typically 8-methoxypsoralen) and UVA. Methoxsalen is used recently in combination with UVA in the therapy of vitiligo, severe psoriasis, cutaneous T-cell lymphoma, mycosis fungoides, and other forms of photosensitivity.<br />
<br />
<br />
<br>There are several forms of treatments: topical, bath, oral and extracorporeal (outside the body) available but by prescription only.<br />
<br />
<br />
<br />
*'''Topical Solution''':<br><br />
This may be used to cure vitiligo. It is applied to the affected area then waited for it dry for few minutes before second application. The treated area is then exposed to UVA for 2hrs later.<br />
<br />
<br />
<br />
*'''Bathwater''':<br><br />
It is used for treatments to small areas, such as hands and feet. The area is treated by soaked in a dilute solution of methoxsalen for half an hour and then exposed to UVA immediately.<br />
<br />
<br />
<br />
*'''Oral preparation''':<br><br />
This is existed as hard and soft gelatine capsules that used to cure mycosis fungoides, vitiligo and posriasis. This may be given twice or three times a week having at least 48 hrs between each treatments.<br />
<br />
<br />
<br />
*'''Extracorporeal''':<br><br />
The white blood cells is removed from the blood and treated in a process called photophersis--methoxsalen along with UVA to control skin problems which caused by cutaneous T-cell lymphoma which is a cancer of the lymph system. After the therapy, the blood cells are returned to the body.<br />
<br><br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html<br><br />
6)[http://ntp-server.niehs.nih.gov/ntp/roc/eleventh/profiles/s104meth.pdf 11th ROC: Methoxsalen with Ultraviolet A Therapy (PUVA)]</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4618
It:Methoxsalen
2006-10-28T14:51:15Z
<p>Qlw05: </p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
The first uses of psoralen-containing plant extracts in photochemotherapy to cure vitiligo recorded date back to 1500B.C. in India and Egypt. The abbreviation of PUVA was first used in 1974 after successful treatment of severe psoriasis using psoranlen (typically 8-methoxypsoralen) and UVA. Methoxsalen is used recently in combination with UVA in the therapy of vitiligo, severe psoriasis, cutaneous T-cell lymphoma, mycosis fungoides, and other forms of photosensitivity.<br />
<br />
<br />
<br>There are several forms of treatments: topical, bath, oral and extracorporeal (outside the body) available but by prescription only.<br />
<br />
<br />
<br />
*'''Topical Solution''':<br><br />
This may be used to cure vitiligo. It is applied to the affected area then waited for it dry for few minutes before second application. The treated area is then exposed to UVA for 2hrs later.<br />
<br />
<br />
<br />
*'''Bathwater''':<br><br />
It is used for treatments to small areas, such as hands and feet. The area is treated by soaked in a dilute solution of methoxsalen for half an hour and then exposed to UVA immediately.<br />
<br />
<br />
<br />
*'''Oral preparation''':<br><br />
This is existed as hard and soft gelatine capsules that used to cure mycosis fungoides, vitiligo and posriasis. This may be given twice or three times a week having at least 48 hrs between each treatments.<br />
<br />
<br />
<br />
*'''Extracorporeal''':<br><br />
The white blood cells is removed from the blood and treated in a process called photophersis--methoxsalen along with UVA to control skin problems which caused by cutaneous T-cell lymphoma which is a cancer of the lymph system. After the therapy, the blood cells are returned to the body.<br />
<br><br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4617
It:Methoxsalen
2006-10-28T14:49:57Z
<p>Qlw05: /* Uses and Dosage */</p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 <br />
ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
The first uses of psoralen-containing plant extracts in photochemotherapy to cure vitiligo recorded date back to 1500B.C. in India and Egypt. The abbreviation of PUVA was first used in 1974 after successful treatment of severe psoriasis using psoranlen (typically 8-methoxypsoralen) and UVA. Methoxsalen is used recently in combination with UVA in the therapy of vitiligo, severe psoriasis, cutaneous T-cell lymphoma, mycosis fungoides, and other forms of photosensitivity.<br />
<br />
<br />
<br>There are several forms of treatments: topical, bath, oral and extracorporeal (outside the body) available but by prescription only.<br />
<br />
<br />
<br />
'''Topical Solution''':<br><br />
This may be used to cure vitiligo. It is applied to the affected area then waited for it dry for few minutes before second application. The treated area is then exposed to UVA for 2hrs later.<br />
<br />
<br />
<br />
'''Bathwater''':<br><br />
It is used for treatments to small areas, such as hands and feet. The area is treated by soaked in a dilute solution of methoxsalen for half an hour and then exposed to UVA immediately.<br />
<br />
<br />
<br />
'''Oral preparation''':<br><br />
This is existed as hard and soft gelatine capsules that used to cure mycosis fungoides, vitiligo and posriasis. This may be given twice or three times a week having at least 48 hrs between each treatments.<br />
<br />
<br />
<br />
'''Extracorporeal''':<br><br />
The white blood cells is removed from the blood and treated in a process called photophersis--methoxsalen along with UVA to control skin problems which caused by cutaneous T-cell lymphoma which is a cancer of the lymph system. After the therapy, the blood cells are returned to the body.<br />
<br><br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4616
It:Methoxsalen
2006-10-28T14:49:09Z
<p>Qlw05: /* Uses and Dosage */</p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 <br />
ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
The first uses of psoralen-containing plant extracts in photochemotherapy to cure vitiligo recorded date back to 1500B.C. in India and Egypt. The abbreviation of PUVA was first used in 1974 after successful treatment of severe psoriasis using psoranlen (typically 8-methoxypsoralen) and UVA. Methoxsalen is used recently in combination with UVA in the therapy of vitiligo, severe psoriasis, cutaneous T-cell lymphoma, mycosis fungoides, and other forms of photosensitivity.<br />
There are several forms of treatments: topical, bath, oral and extracorporeal (outside the body) available but by prescription only.<br />
<br />
<br />
<br />
'''Topical Solution''':<br><br />
This may be used to cure vitiligo. It is applied to the affected area then waited for it dry for few minutes before second application. The treated area is then exposed to UVA for 2hrs later.<br />
<br />
<br />
<br />
'''Bathwater''':<br><br />
It is used for treatments to small areas, such as hands and feet. The area is treated by soaked in a dilute solution of methoxsalen for half an hour and then exposed to UVA immediately.<br />
<br />
<br />
<br />
'''Oral preparation''':<br><br />
This is existed as hard and soft gelatine capsules that used to cure mycosis fungoides, vitiligo and posriasis. This may be given twice or three times a week having at least 48 hrs between each treatments.<br />
<br />
<br />
<br />
'''Extracorporeal''':<br><br />
The white blood cells is removed from the blood and treated in a process called photophersis--methoxsalen along with UVA to control skin problems which caused by cutaneous T-cell lymphoma which is a cancer of the lymph system. After the therapy, the blood cells are returned to the body.<br />
<br><br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4611
It:Methoxsalen
2006-10-28T13:49:58Z
<p>Qlw05: </p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 <br />
ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;<br />
Soluble in acetone, acetic acid, propylene glycol, and benzene;<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|-<br />
! Sensitivity<br />
| Sensitive to air and light;<br />
hydrolysed easily<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
It absorbs ultraviolet light, especially UVA wavelengths (320nm - 400nm). Methoxsalen is a photosensitising agent which can produce phototoxic erythema, when applying excess exposure to the skin that may result in hyperpigmentation and skin thickening. The UVA radiation also causes photochemical reaction that conduce DNA adducts forming between methoxsalen and pyrimidine bases.<br />
<br><br />
<br />
<br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Methoxsalen&diff=4609
It:Methoxsalen
2006-10-28T13:25:55Z
<p>Qlw05: </p>
<hr />
<div>==3D Structure of Methoxsalen==<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Fri Oct 20 13:03:31 GMT Standard Time 2006<br />
ATOM 1 O1 MOL 1 14.448 14.733 -0.004 1.00 0.00 <br />
ATOM 2 C2 MOL 1 13.218 15.463 -0.005 1.00 0.00 ATOM 3 C3 MOL 1 14.316 13.321 -0.005 1.00 0.00 <br />
ATOM 4 C4 MOL 1 15.435 12.588 -0.004 1.00 0.00 <br />
ATOM 5 C5 MOL 1 13.014 12.603 -0.000 1.00 0.00 <br />
ATOM 6 C6 MOL 1 15.358 11.104 -0.005 1.00 0.00 <br />
ATOM 7 O7 MOL 1 16.680 13.257 -0.003 1.00 0.00 <br />
ATOM 8 C8 MOL 1 12.982 11.296 -0.003 1.00 0.00 <br />
ATOM 9 O9 MOL 1 11.700 13.147 0.007 1.00 0.00 <br />
ATOM 10 C10 MOL 1 14.176 10.484 -0.006 1.00 0.00 <br />
ATOM 11 C11 MOL 1 16.569 10.328 -0.000 1.00 0.00 <br />
ATOM 12 C12 MOL 1 17.826 12.419 0.004 1.00 0.00 <br />
ATOM 13 C13 MOL 1 11.646 10.851 0.002 1.00 0.00 <br />
ATOM 14 C14 MOL 1 10.895 11.955 0.009 1.00 0.00 <br />
ATOM 15 C15 MOL 1 17.740 10.951 0.005 1.00 0.00 <br />
ATOM 16 O16 MOL 1 18.946 12.942 0.010 1.00 0.00 <br />
TER<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br><br />
----<br />
<br><br />
<font color=red><font size=5>What is Methoxsalen?</font color></font size><br><br><br />
<font color=brown>''3D structure of Methoxsalen:''</font><br><br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
ATOM 1 C 0 -0.431 2.805 -0.885 0.00 0.00 C+0<br />
ATOM 2 O 0 -0.438 2.207 0.412 0.00 0.00 O+0<br />
ATOM 3 C 0 -0.497 0.861 0.225 0.00 0.00 C+0<br />
ATOM 4 C 0 0.674 0.124 0.113 0.00 0.00 C+0<br />
ATOM 5 C 0 0.612 -1.271 -0.081 0.00 0.00 C+0<br />
ATOM 6 C 0 -0.622 -1.915 -0.162 0.00 0.00 C+0<br />
ATOM 7 C 0 -1.789 -1.170 -0.049 0.00 0.00 C+0<br />
ATOM 8 C 0 -1.731 0.223 0.151 0.00 0.00 C+0<br />
ATOM 9 O 0 -3.003 0.668 0.221 0.00 0.00 O+0<br />
ATOM 10 C 0 -3.875 -0.345 0.080 0.00 0.00 C+0<br />
ATOM 11 C 0 -3.220 -1.501 -0.084 0.00 0.00 C+0<br />
ATOM 12 C 0 1.862 -2.029 -0.197 0.00 0.00 C+0<br />
ATOM 13 C 0 3.034 -1.350 -0.112 0.00 0.00 C+0<br />
ATOM 14 C 0 3.023 0.048 0.083 0.00 0.00 C+0<br />
ATOM 15 O 0 4.083 0.644 0.158 0.00 0.00 O+0<br />
ATOM 16 O 0 1.877 0.737 0.189 0.00 0.00 O+0<br />
ATOM 17 H 0 0.438 2.454 -1.442 0.00 0.00 H+0<br />
ATOM 18 H 0 -1.340 2.528 -1.418 0.00 0.00 H+0<br />
ATOM 19 H 0 -0.384 3.889 -0.786 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.671 -2.984 -0.311 0.00 0.00 H+0<br />
ATOM 21 H 0 -4.950 -0.242 0.100 0.00 0.00 H+0<br />
ATOM 22 H 0 -3.656 -2.480 -0.222 0.00 0.00 H+0<br />
ATOM 23 H 0 1.851 -3.098 -0.346 0.00 0.00 H+0<br />
ATOM 24 H 0 3.973 -1.878 -0.193 0.00 0.00 H+0<br />
CONECT 1 2 17 18 19 NONE 29<br />
CONECT 2 1 3 0 0 NONE 30<br />
CONECT 3 2 8 4 0 NONE 31<br />
CONECT 4 3 16 5 0 NONE 32<br />
CONECT 5 4 6 12 0 NONE 33<br />
CONECT 6 5 7 20 0 NONE 34<br />
CONECT 7 6 11 8 0 NONE 35<br />
CONECT 8 7 3 9 0 NONE 36<br />
CONECT 9 8 10 0 0 NONE 37<br />
CONECT 10 9 11 21 0 NONE 38<br />
CONECT 11 10 7 22 0 NONE 39<br />
CONECT 12 5 13 23 0 NONE 40<br />
CONECT 13 12 14 24 0 NONE 41<br />
CONECT 14 13 15 16 0 NONE 42<br />
CONECT 15 14 0 0 0 NONE 43<br />
CONECT 16 14 4 0 0 NONE 44<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br><br />
<br />
<font color=brown>''2D structure of Methoxsalen:''</font><br><br><br />
[[Image:methox.gif|middle|2D structure of Methoxsalen]]<br />
<br><br><br />
<br />
{| border="1"<br />
|+ '''- Physical & Chemical properties<sup>1</sup> -'''<br />
! Chemical name<br />
| 9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one<br />
|-<br />
! Molecular formular<br />
|C<sub>12</sub>H<sub>8</sub>O<sub>4</sub><br />
|-<br />
! Molecular weight<br />
| 216.19 g/mol<br />
|-<br />
! State<br />
| Solid<br />
|-<br />
! Appearance<br />
| White to yellow powder<br />
White to cream-coloured odorless solid that forms needle-like crystals<br />
|-<br />
! Solubility<br />
| Clear to very slightly hazy yellow solution at 200mg plus 4ml of chloroform<br />
Insoluble in cold water;Soluble in acetone, acetic acid, propylene glycol, and benzene<br />
Soluble in boiling water and ether sparingly<br />
|-<br />
! Elemental analysis<br />
| 65.3 - 68.0% Carbon<br />
|-<br />
! Purity by gas chromatography<br />
| Not less than 98%<br />
|-<br />
! Melting point<br />
| 148 Degree<br />
|}<br />
<br><br />
<font color=brown>''FT NMR of Methoxsalen:''</font><br><br><br />
[[Image:nmr.JPG|middle|FT NMR of Methoxsalen]]<br />
<br />
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant. It belongs to a group of compounds known as psoralens or furocoumarins. It is a photoactive substance and produces its effects when exposed to ultraviolet (UVA) light. Methoxsalen causes damage to the DNA of cells, ultimately causing their death<sup>2</sup>.<br />
<br><br />
<br><br />
<font color=red><font size=5>What is Methoxsalen used for?</font color></font size><br><br />
<br><br />
Methoxsalen is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called psoralen plus ultraviolet light A (PUVA) to treat vitiligo, a disease in which skin color is lost<sup>3</sup>.<br><br />
Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content of DNA correlates with the degree of Methoxsalen-induced cross-linking, meaning after activation it binds preferentially to the guanine and cytosine bases of DNA, leading its cross-linking, thus inhibiting DNA synthesis and function. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.<br><br />
It is also a drug that has been clinically proven to decrease smoking by interacting with and blocking the action of a protein that breaks down nicotine<sup>4</sup>. People who have nicotine addiction continue to smoke to maintain high nicotine levels in the brain. Methoxsalen specifically prevents the protein cytochrome P450 2A6 from degrading nicotine. Cytochrome P450 2A6 also breaks down carcinogens found in tobacco to more harmful chemicals that can cause cancer.<br />
<br />
<br />
==Uses and Dosage==<br />
<br />
<br />
==Contraindications and Warnings==<br />
<br />
*Methoxsalen is a very strong medicine that causes increased sensitivity of the skin to sunlight. If not used as directed by a doctor, it can cause serious sunburns, and in reported cases, increased risk of cataracts and skin cancer. <br />
*It is best to exercise caution when prescribing to pregnant mothers, as studies in animals have shown that methoxsalen can cause birth defects and death of the fetus. <br />
*Side effects are more likely to occur in young children, due to higher sensitivity to the drug effects.<br />
*The chances of side effects are increased if methoxsalen is used in combination with:<br />
**Arsenicals, x-rays and cancer medicines<br />
**Anthralin <br />
**Bacteriostatic soaps<br />
**Certain organic dyes (such as methylene blue, methyl orange, rose bengal, and toluidine blue)<br />
**Griseofulvin <br />
**Nalidixic acid<br />
**Phenothiazines <br />
**Sulfonamides <br />
**Tetracyclines <br />
**Thiazide diuretics<br />
*Do inform your doctor if you have other medical problems, such as<sup>[5]</sup>:<br />
**Allergy to sunlight<br />
**Albinism<br />
**Lupus erythematosus <br />
**Porphyria cutanea tarda<br />
**Xeroderma pigmentosum<br />
**Variegate porphyria <br />
**Skin cancer (history of) <br />
**Skin conditions (other)<br />
**Stomach problems<br />
**Eye problems, such as cataracts or loss of the lens of the eye<br />
**Heart or blood vessel disease (severe)<br />
**Liver disease<br />
<br />
<br />
<br />
<br />
==Side Effects==<br />
<br />
Consult your doctor if side effects occur:<br />
*Fever<br />
*Irregular heartbeat<br />
*Redness or pain at catheter site<br />
<br />
Methoxsalen usually causes slight reddening of the skin 24-48 hours after the treatment; this is usually no cause for concern. However, if the skin becomes sore or blistered, consult your doctor immediately. <br />
<br />
<br />
Symptoms of overdose or prolonged treatment include<sup>[5]</sup>:<br />
*Blistering and peeling of skin<br />
*Increased risk of skin cancer<br />
*Premature aging<br />
<br />
<br />
<br />
<font color=red><font size=5>References</font color></font size><br><br><br />
1)[http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIAL/M3501 2006 Sigma-Aldrich Co]<br><br />
2)[http://www.ufscc.ufl.edu/Patient/drug_dictionary.aspx?id=791 University of Florida Shands Cancer Center]<br><br />
3)[http://www.drugs.com Drugs information online]<br><br />
4)[http://www.medicalnewstoday.com/medicalnews.php?newsid=28864 Medical News Today]<br><br />
5)http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202357.html</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4305
It:Rapamycin
2006-10-26T14:16:04Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:Rapamycin.gif|50|2D structure of Rapamycin|50]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties <sup>1</sup><br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin inhibits the production of T cells, and also inhibits the production of antibodies. It binds to the binding protein, such as FKBP-12 to generate an immunosuppressive complex.<br />
This complex binds to and then inhibits the activation of the mammalian target of rapamycin, mTOR. This inhibition suppresses cytokine inhibiting the progression from the G1 to the S phase of the cell cycle.<br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
The rapamycin is thought to target the proteins <sup>8</sup>:<br />
(1) 70-kD S6 protein kinase p70<sup>S6K</sup><br />
(2) Eukaryotic initiation factor eIF-4F<br />
(3) G1-controlling cyclin-dependent kinase (cdk) proteins <br />
(4) Kinase inhibitory protein Kip1 (p27<sup>kip</sup>), which blocks cell progression to the S phase.<br />
<br />
The diagram below shows how the mechanism steps of how rapamycin works:<br />
<br />
'''How Rapamycin works'''<br />
[[Image:mechanism.gif]]<br />
<br />
''Note:''<br />
SRL = Sirolimus (rapamycin)<br />
mTOR = mammalian target of rapamycin<br />
CsA = Cyclosporine<br />
PTKs = protein tyrosine kinases<br />
p34<sup>cdc2</sup> = a kinase<br />
<br />
Below is the 3D structure of the binding protein, FKBP 12.6 in complex with a rapamycin molecule: <br />
<br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Thu Oct 26 13:37:31 GMT Standard Time 2006<br />
CRYST1 45.696 49.288 51.694 90.00 90.00 90.00 P212121<br />
ATOM 1 N GLY A 1 -6.981 2.196 -6.695 1.00 0.00 <br />
ATOM 2 CA GLY A 1 -8.065 1.703 -5.797 1.00 0.00 <br />
ATOM 3 C GLY A 1 -9.417 2.193 -6.277 1.00 0.00 <br />
ATOM 4 O GLY A 1 -9.620 2.391 -7.474 1.00 0.00 <br />
ATOM 5 N VAL A 2 -10.341 2.395 -5.345 1.00 0.00 <br />
ATOM 6 CA VAL A 2 -11.672 2.874 -5.688 1.00 0.00 <br />
ATOM 7 C VAL A 2 -11.896 4.253 -5.093 1.00 0.00 <br />
ATOM 8 O VAL A 2 -11.650 4.467 -3.906 1.00 0.00 <br />
ATOM 9 CB VAL A 2 -12.775 1.964 -5.119 1.00 0.00 <br />
ATOM 10 CG1 VAL A 2 -14.094 2.249 -5.822 1.00 0.00 <br />
ATOM 11 CG2 VAL A 2 -12.376 0.517 -5.254 1.00 0.00 <br />
ATOM 12 N GLU A 3 -12.355 5.183 -5.923 1.00 0.00 <br />
ATOM 13 CA GLU A 3 -12.654 6.535 -5.471 1.00 0.00 <br />
ATOM 14 C GLU A 3 -14.163 6.708 -5.554 1.00 0.00 <br />
ATOM 15 O GLU A 3 -14.802 6.200 -6.474 1.00 0.00 <br />
ATOM 16 CB GLU A 3 -11.955 7.572 -6.348 1.00 0.00 <br />
ATOM 17 CG GLU A 3 -10.439 7.498 -6.286 1.00 0.00 <br />
ATOM 18 CD GLU A 3 -9.773 8.693 -6.944 1.00 0.00 <br />
ATOM 19 OE1 GLU A 3 -10.120 9.004 -8.106 1.00 0.00 <br />
ATOM 20 OE2 GLU A 3 -8.902 9.321 -6.299 1.00 0.00 <br />
ATOM 21 N ILE A 4 -14.724 7.428 -4.590 1.00 0.00 <br />
ATOM 22 CA ILE A 4 -16.160 7.645 -4.517 1.00 0.00 <br />
ATOM 23 C ILE A 4 -16.539 9.118 -4.648 1.00 0.00 <br />
ATOM 24 O ILE A 4 -15.943 9.977 -4.004 1.00 0.00 <br />
ATOM 25 CB ILE A 4 -16.728 7.152 -3.150 1.00 0.00 <br />
ATOM 26 CG1 ILE A 4 -16.327 5.697 -2.890 1.00 0.00 <br />
ATOM 27 CG2 ILE A 4 -18.232 7.308 -3.120 1.00 0.00 <br />
ATOM 28 CD1 ILE A 4 -16.872 4.708 -3.892 1.00 0.00 <br />
ATOM 29 N GLU A 5 -17.527 9.393 -5.494 1.00 0.00 <br />
ATOM 30 CA GLU A 5 -18.054 10.744 -5.669 1.00 0.00 <br />
ATOM 31 C GLU A 5 -19.552 10.561 -5.505 1.00 0.00 <br />
ATOM 32 O GLU A 5 -20.210 9.962 -6.357 1.00 0.00 <br />
ATOM 33 CB GLU A 5 -17.748 11.307 -7.060 1.00 0.00 <br />
ATOM 34 CG GLU A 5 -16.281 11.588 -7.305 1.00 0.00 <br />
ATOM 35 CD GLU A 5 -16.027 12.152 -8.688 1.00 0.00 <br />
ATOM 36 OE1 GLU A 5 -16.467 13.290 -8.959 1.00 0.00 <br />
ATOM 37 OE2 GLU A 5 -15.390 11.452 -9.505 1.00 0.00 <br />
ATOM 38 N THR A 6 -20.086 11.064 -4.401 1.00 0.00 <br />
ATOM 39 CA THR A 6 -21.503 10.918 -4.115 1.00 0.00 <br />
ATOM 40 C THR A 6 -22.435 11.594 -5.113 1.00 0.00 <br />
ATOM 41 O THR A 6 -22.225 12.741 -5.517 1.00 0.00 <br />
ATOM 42 CB THR A 6 -21.819 11.427 -2.699 1.00 0.00 <br />
ATOM 43 OG1 THR A 6 -21.153 10.595 -1.743 1.00 0.00 <br />
ATOM 44 CG2 THR A 6 -23.321 11.402 -2.440 1.00 0.00 <br />
ATOM 45 N ILE A 7 -23.461 10.853 -5.514 1.00 0.00 <br />
ATOM 46 CA ILE A 7 -24.471 11.341 -6.443 1.00 0.00 <br />
ATOM 47 C ILE A 7 -25.656 11.812 -5.601 1.00 0.00 <br />
ATOM 48 O ILE A 7 -26.213 12.891 -5.818 1.00 0.00 <br />
ATOM 49 CB ILE A 7 -24.909 10.212 -7.401 1.00 0.00 <br />
ATOM 50 CG1 ILE A 7 -23.758 9.896 -8.365 1.00 0.00 <br />
ATOM 51 CG2 ILE A 7 -26.173 10.614 -8.163 1.00 0.00 <br />
ATOM 52 CD1 ILE A 7 -24.015 8.709 -9.281 1.00 0.00 <br />
ATOM 53 N SER A 8 -26.033 10.977 -4.639 1.00 0.00 <br />
ATOM 54 CA SER A 8 -27.119 11.267 -3.707 1.00 0.00 <br />
ATOM 55 C SER A 8 -26.659 10.688 -2.380 1.00 0.00 <br />
ATOM 56 O SER A 8 -26.206 9.549 -2.323 1.00 0.00 <br />
ATOM 57 CB SER A 8 -28.422 10.596 -4.144 1.00 0.00 <br />
ATOM 58 OG SER A 8 -29.022 11.290 -5.223 1.00 0.00 <br />
ATOM 59 N PRO A 9 -26.773 11.462 -1.292 1.00 0.00 <br />
ATOM 60 CA PRO A 9 -26.339 10.972 0.020 1.00 0.00 <br />
ATOM 61 C PRO A 9 -27.220 9.882 0.618 1.00 0.00 <br />
ATOM 62 O PRO A 9 -28.409 9.801 0.324 1.00 0.00 <br />
ATOM 63 CB PRO A 9 -26.321 12.244 0.868 1.00 0.00 <br />
ATOM 64 CG PRO A 9 -27.477 13.024 0.300 1.00 0.00 <br />
ATOM 65 CD PRO A 9 -27.298 12.837 -1.201 1.00 0.00 <br />
ATOM 66 N GLY A 10 -26.617 9.034 1.446 1.00 0.00 <br />
ATOM 67 CA GLY A 10 -27.365 7.973 2.098 1.00 0.00 <br />
ATOM 68 C GLY A 10 -27.791 8.483 3.463 1.00 0.00 <br />
ATOM 69 O GLY A 10 -27.748 9.688 3.707 1.00 0.00 <br />
ATOM 70 N ASP A 11 -28.198 7.595 4.363 1.00 0.00 <br />
ATOM 71 CA ASP A 11 -28.605 8.063 5.682 1.00 0.00 <br />
ATOM 72 C ASP A 11 -27.363 8.404 6.509 1.00 0.00 <br />
ATOM 73 O ASP A 11 -27.462 8.997 7.583 1.00 0.00 <br />
ATOM 74 CB ASP A 11 -29.469 7.014 6.394 1.00 0.00 <br />
ATOM 75 CG ASP A 11 -28.717 5.729 6.695 1.00 0.00 <br />
ATOM 76 OD1 ASP A 11 -27.485 5.676 6.484 1.00 0.00 <br />
ATOM 77 OD2 ASP A 11 -29.373 4.771 7.158 1.00 0.00 <br />
ATOM 78 N GLY A 12 -26.196 8.029 5.990 1.00 0.00 <br />
ATOM 79 CA GLY A 12 -24.941 8.314 6.664 1.00 0.00 <br />
ATOM 80 C GLY A 12 -24.631 7.519 7.920 1.00 0.00 <br />
ATOM 81 O GLY A 12 -23.743 7.898 8.690 1.00 0.00 <br />
ATOM 82 N ARG A 13 -25.335 6.415 8.137 1.00 0.00 <br />
ATOM 83 CA ARG A 13 -25.084 5.619 9.329 1.00 0.00 <br />
ATOM 84 C ARG A 13 -25.326 4.126 9.156 1.00 0.00 <br />
ATOM 85 O ARG A 13 -24.781 3.320 9.907 1.00 0.00 <br />
ATOM 86 CB ARG A 13 -25.919 6.156 10.498 1.00 0.00 <br />
ATOM 87 CG ARG A 13 -27.396 6.326 10.197 1.00 0.00 <br />
ATOM 88 CD ARG A 13 -28.075 7.146 11.295 1.00 0.00 <br />
ATOM 89 NE ARG A 13 -29.469 7.446 10.981 1.00 0.00 <br />
ATOM 90 CZ ARG A 13 -30.430 6.533 10.895 1.00 0.00 <br />
ATOM 91 NH1 ARG A 13 -30.152 5.252 11.103 1.00 0.00 <br />
ATOM 92 NH2 ARG A 13 -31.669 6.897 10.593 1.00 0.00 <br />
ATOM 93 N THR A 14 -26.126 3.755 8.163 1.00 0.00 <br />
ATOM 94 CA THR A 14 -26.420 2.346 7.925 1.00 0.00 <br />
ATOM 95 C THR A 14 -25.571 1.781 6.791 1.00 0.00 <br />
ATOM 96 O THR A 14 -25.933 1.895 5.619 1.00 0.00 <br />
ATOM 97 CB THR A 14 -27.907 2.141 7.586 1.00 0.00 <br />
ATOM 98 OG1 THR A 14 -28.718 2.756 8.599 1.00 0.00 <br />
ATOM 99 CG2 THR A 14 -28.236 0.657 7.519 1.00 0.00 <br />
ATOM 100 N PHE A 15 -24.445 1.166 7.150 1.00 0.00 <br />
ATOM 101 CA PHE A 15 -23.527 0.588 6.174 1.00 0.00 <br />
ATOM 102 C PHE A 15 -23.654 -0.930 6.104 1.00 0.00 <br />
ATOM 103 O PHE A 15 -24.151 -1.569 7.035 1.00 0.00 <br />
ATOM 104 CB PHE A 15 -22.074 0.944 6.521 1.00 0.00 <br />
ATOM 105 CG PHE A 15 -21.800 2.422 6.558 1.00 0.00 <br />
ATOM 106 CD1 PHE A 15 -22.182 3.186 7.656 1.00 0.00 <br />
ATOM 107 CD2 PHE A 15 -21.176 3.052 5.488 1.00 0.00 <br />
ATOM 108 CE1 PHE A 15 -21.943 4.564 7.689 1.00 0.00 <br />
ATOM 109 CE2 PHE A 15 -20.933 4.429 5.508 1.00 0.00 <br />
ATOM 110 CZ PHE A 15 -21.318 5.184 6.614 1.00 0.00 <br />
ATOM 111 N PRO A 16 -23.198 -1.529 4.994 1.00 0.00 <br />
ATOM 112 CA PRO A 16 -23.272 -2.984 4.832 1.00 0.00 <br />
ATOM 113 C PRO A 16 -22.464 -3.715 5.904 1.00 0.00 <br />
ATOM 114 O PRO A 16 -21.291 -3.410 6.120 1.00 0.00 <br />
ATOM 115 CB PRO A 16 -22.694 -3.205 3.433 1.00 0.00 <br />
ATOM 116 CG PRO A 16 -23.072 -1.940 2.713 1.00 0.00 <br />
ATOM 117 CD PRO A 16 -22.744 -0.887 3.748 1.00 0.00 <br />
ATOM 118 N LYS A 17 -23.102 -4.668 6.578 1.00 0.00 <br />
ATOM 119 CA LYS A 17 -22.435 -5.451 7.614 1.00 0.00 <br />
ATOM 120 C LYS A 17 -21.978 -6.781 7.019 1.00 0.00 <br />
ATOM 121 O LYS A 17 -22.447 -7.190 5.959 1.00 0.00 <br />
ATOM 122 CB LYS A 17 -23.385 -5.729 8.782 1.00 0.00 <br />
ATOM 123 CG LYS A 17 -23.891 -4.500 9.515 1.00 0.00 <br />
ATOM 124 CD LYS A 17 -24.763 -4.914 10.696 1.00 0.00 <br />
ATOM 125 CE LYS A 17 -25.272 -3.707 11.472 1.00 0.00 <br />
ATOM 126 NZ LYS A 17 -26.068 -4.106 12.674 1.00 0.00 <br />
ATOM 127 N LYS A 18 -21.072 -7.460 7.713 1.00 0.00 <br />
ATOM 128 CA LYS A 18 -20.565 -8.745 7.243 1.00 0.00 <br />
ATOM 129 C LYS A 18 -21.705 -9.742 7.046 1.00 0.00 <br />
ATOM 130 O LYS A 18 -22.583 -9.871 7.896 1.00 0.00 <br />
ATOM 131 CB LYS A 18 -19.559 -9.310 8.247 1.00 0.00 <br />
ATOM 132 CG LYS A 18 -18.379 -8.395 8.523 1.00 0.00 <br />
ATOM 133 CD LYS A 18 -17.434 -9.010 9.547 1.00 0.00 <br />
ATOM 134 CE LYS A 18 -16.263 -8.085 9.851 1.00 0.00 <br />
ATOM 135 NZ LYS A 18 -15.335 -8.691 10.844 1.00 0.00 <br />
ATOM 136 N GLY A 19 -21.692 -10.435 5.912 1.00 0.00 <br />
ATOM 137 CA GLY A 19 -22.726 -11.418 5.637 1.00 0.00 <br />
ATOM 138 C GLY A 19 -24.002 -10.886 5.009 1.00 0.00 <br />
ATOM 139 O GLY A 19 -24.752 -11.645 4.390 1.00 0.00 <br />
ATOM 140 N GLN A 20 -24.262 -9.590 5.165 1.00 0.00 <br />
ATOM 141 CA GLN A 20 -25.464 -8.992 4.596 1.00 0.00 <br />
ATOM 142 C GLN A 20 -25.453 -9.062 3.079 1.00 0.00 <br />
ATOM 143 O GLN A 20 -24.400 -9.216 2.457 1.00 0.00 <br />
ATOM 144 CB GLN A 20 -25.602 -7.527 5.016 1.00 0.00 <br />
ATOM 145 CG GLN A 20 -26.018 -7.319 6.456 1.00 0.00 <br />
ATOM 146 CD GLN A 20 -26.535 -5.914 6.703 1.00 0.00 <br />
ATOM 147 OE1 GLN A 20 -25.795 -4.937 6.592 1.00 0.00 <br />
ATOM 148 NE2 GLN A 20 -27.818 -5.806 7.030 1.00 0.00 <br />
ATOM 149 N THR A 21 -26.637 -8.950 2.490 1.00 0.00 <br />
ATOM 150 CA THR A 21 -26.773 -8.978 1.043 1.00 0.00 <br />
ATOM 151 C THR A 21 -27.114 -7.571 0.582 1.00 0.00 <br />
ATOM 152 O THR A 21 -28.130 -7.004 0.990 1.00 0.00 <br />
ATOM 153 CB THR A 21 -27.896 -9.934 0.592 1.00 0.00 <br />
ATOM 154 OG1 THR A 21 -27.606 -11.263 1.044 1.00 0.00 <br />
ATOM 155 CG2 THR A 21 -28.009 -9.935 -0.922 1.00 0.00 <br />
ATOM 156 N CYS A 22 -26.250 -7.002 -0.251 1.00 0.00 <br />
ATOM 157 CA CYS A 22 -26.479 -5.662 -0.765 1.00 0.00 <br />
ATOM 158 C CYS A 22 -27.405 -5.709 -1.970 1.00 0.00 <br />
ATOM 159 O CYS A 22 -27.232 -6.537 -2.866 1.00 0.00 <br />
ATOM 160 CB CYS A 22 -25.155 -5.012 -1.172 1.00 0.00 <br />
ATOM 161 SG CYS A 22 -24.056 -4.617 0.206 1.00 0.00 <br />
ATOM 162 N VAL A 23 -28.405 -4.835 -1.972 1.00 0.00 <br />
ATOM 163 CA VAL A 23 -29.329 -4.740 -3.093 1.00 0.00 <br />
ATOM 164 C VAL A 23 -28.961 -3.414 -3.736 1.00 0.00 <br />
ATOM 165 O VAL A 23 -29.121 -2.349 -3.137 1.00 0.00 <br />
ATOM 166 CB VAL A 23 -30.798 -4.711 -2.640 1.00 0.00 <br />
ATOM 167 CG1 VAL A 23 -31.710 -4.703 -3.861 1.00 0.00 <br />
ATOM 168 CG2 VAL A 23 -31.097 -5.921 -1.758 1.00 0.00 <br />
ATOM 169 N VAL A 24 -28.458 -3.489 -4.958 1.00 0.00 <br />
ATOM 170 CA VAL A 24 -28.003 -2.305 -5.665 1.00 0.00 <br />
ATOM 171 C VAL A 24 -28.488 -2.194 -7.105 1.00 0.00 <br />
ATOM 172 O VAL A 24 -28.914 -3.174 -7.716 1.00 0.00 <br />
ATOM 173 CB VAL A 24 -26.449 -2.289 -5.700 1.00 0.00 <br />
ATOM 174 CG1 VAL A 24 -25.945 -1.234 -6.669 1.00 0.00 <br />
ATOM 175 CG2 VAL A 24 -25.897 -2.045 -4.307 1.00 0.00 <br />
ATOM 176 N HIS A 25 -28.430 -0.973 -7.624 1.00 0.00 <br />
ATOM 177 CA HIS A 25 -28.737 -0.711 -9.015 1.00 0.00 <br />
ATOM 178 C HIS A 25 -27.410 -0.147 -9.512 1.00 0.00 <br />
ATOM 179 O HIS A 25 -26.775 0.644 -8.817 1.00 0.00 <br />
ATOM 180 CB HIS A 25 -29.841 0.328 -9.171 1.00 0.00 <br />
ATOM 181 CG HIS A 25 -31.102 -0.227 -9.753 1.00 0.00 <br />
ATOM 182 ND1 HIS A 25 -31.106 -1.070 -10.844 1.00 0.00 <br />
ATOM 183 CD2 HIS A 25 -32.399 -0.061 -9.401 1.00 0.00 <br />
ATOM 184 CE1 HIS A 25 -32.350 -1.399 -11.138 1.00 0.00 <br />
ATOM 185 NE2 HIS A 25 -33.154 -0.801 -10.278 1.00 0.00 <br />
ATOM 186 N TYR A 26 -26.967 -0.558 -10.691 1.00 0.00 <br />
ATOM 187 CA TYR A 26 -25.700 -0.054 -11.189 1.00 0.00 <br />
ATOM 188 C TYR A 26 -25.663 0.063 -12.704 1.00 0.00 <br />
ATOM 189 O TYR A 26 -26.477 -0.525 -13.415 1.00 0.00 <br />
ATOM 190 CB TYR A 26 -24.557 -0.970 -10.723 1.00 0.00 <br />
ATOM 191 CG TYR A 26 -24.487 -2.281 -11.480 1.00 0.00 <br />
ATOM 192 CD1 TYR A 26 -23.818 -2.367 -12.703 1.00 0.00 <br />
ATOM 193 CD2 TYR A 26 -25.132 -3.423 -11.002 1.00 0.00 <br />
ATOM 194 CE1 TYR A 26 -23.791 -3.555 -13.431 1.00 0.00 <br />
ATOM 195 CE2 TYR A 26 -25.118 -4.617 -11.726 1.00 0.00 <br />
ATOM 196 CZ TYR A 26 -24.445 -4.673 -12.942 1.00 0.00 <br />
ATOM 197 OH TYR A 26 -24.434 -5.841 -13.671 1.00 0.00 <br />
ATOM 198 N THR A 27 -24.697 0.840 -13.174 1.00 0.00 <br />
ATOM 199 CA THR A 27 -24.449 1.055 -14.587 1.00 0.00 <br />
ATOM 200 C THR A 27 -22.928 1.057 -14.665 1.00 0.00 <br />
ATOM 201 O THR A 27 -22.264 1.819 -13.956 1.00 0.00 <br />
ATOM 202 CB THR A 27 -24.992 2.416 -15.072 1.00 0.00 <br />
ATOM 203 OG1 THR A 27 -26.420 2.441 -14.928 1.00 0.00 <br />
ATOM 204 CG2 THR A 27 -24.624 2.646 -16.535 1.00 0.00 <br />
ATOM 205 N GLY A 28 -22.382 0.180 -15.501 1.00 0.00 <br />
ATOM 206 CA GLY A 28 -20.939 0.086 -15.638 1.00 0.00 <br />
ATOM 207 C GLY A 28 -20.472 0.667 -16.951 1.00 0.00 <br />
ATOM 208 O GLY A 28 -21.100 0.468 -17.994 1.00 0.00 <br />
ATOM 209 N MET A 29 -19.352 1.371 -16.908 1.00 0.00 <br />
ATOM 210 CA MET A 29 -18.826 2.009 -18.101 1.00 0.00 <br />
ATOM 211 C MET A 29 -17.303 2.036 -18.084 1.00 0.00 <br />
ATOM 212 O MET A 29 -16.690 2.198 -17.028 1.00 0.00 <br />
ATOM 213 CB MET A 29 -19.385 3.432 -18.163 1.00 0.00 <br />
ATOM 214 CG MET A 29 -18.848 4.325 -19.251 1.00 0.00 <br />
ATOM 215 SD MET A 29 -19.532 5.992 -19.016 1.00 0.00 <br />
ATOM 216 CE MET A 29 -18.323 6.720 -17.930 1.00 0.00 <br />
ATOM 217 N LEU A 30 -16.690 1.861 -19.248 1.00 0.00 <br />
ATOM 218 CA LEU A 30 -15.235 1.913 -19.343 1.00 0.00 <br />
ATOM 219 C LEU A 30 -14.853 3.387 -19.268 1.00 0.00 <br />
ATOM 220 O LEU A 30 -15.529 4.229 -19.857 1.00 0.00 <br />
ATOM 221 CB LEU A 30 -14.762 1.331 -20.679 1.00 0.00 <br />
ATOM 222 CG LEU A 30 -15.062 -0.143 -20.933 1.00 0.00 <br />
ATOM 223 CD1 LEU A 30 -14.700 -0.502 -22.371 1.00 0.00 <br />
ATOM 224 CD2 LEU A 30 -14.275 -0.990 -19.947 1.00 0.00 <br />
ATOM 225 N GLN A 31 -13.789 3.714 -18.543 1.00 0.00 <br />
ATOM 226 CA GLN A 31 -13.381 5.111 -18.432 1.00 0.00 <br />
ATOM 227 C GLN A 31 -13.116 5.621 -19.841 1.00 0.00 <br />
ATOM 228 O GLN A 31 -12.319 5.033 -20.568 1.00 0.00 <br />
ATOM 229 CB GLN A 31 -12.107 5.249 -17.595 1.00 0.00 <br />
ATOM 230 CG GLN A 31 -11.789 6.685 -17.216 1.00 0.00 <br />
ATOM 231 CD GLN A 31 -10.349 6.885 -16.801 1.00 0.00 <br />
ATOM 232 OE1 GLN A 31 -9.782 6.078 -16.073 1.00 0.00 <br />
ATOM 233 NE2 GLN A 31 -9.755 7.990 -17.249 1.00 0.00 <br />
ATOM 234 N ASN A 32 -13.784 6.706 -20.227 1.00 0.00 <br />
ATOM 235 CA ASN A 32 -13.610 7.268 -21.563 1.00 0.00 <br />
ATOM 236 C ASN A 32 -13.988 6.222 -22.620 1.00 0.00 <br />
ATOM 237 O ASN A 32 -13.457 6.218 -23.730 1.00 0.00 <br />
ATOM 238 CB ASN A 32 -12.156 7.717 -21.757 1.00 0.00 <br />
ATOM 239 CG ASN A 32 -11.724 8.764 -20.736 1.00 0.00 <br />
ATOM 240 OD1 ASN A 32 -10.536 8.899 -20.437 1.00 0.00 <br />
ATOM 241 ND2 ASN A 32 -12.689 9.514 -20.206 1.00 0.00 <br />
ATOM 242 N GLY A 33 -14.907 5.332 -22.262 1.00 0.00 <br />
ATOM 243 CA GLY A 33 -15.348 4.299 -23.183 1.00 0.00 <br />
ATOM 244 C GLY A 33 -16.858 4.153 -23.140 1.00 0.00 <br />
ATOM 245 O GLY A 33 -17.566 5.050 -22.680 1.00 0.00 <br />
ATOM 246 N LYS A 34 -17.356 3.013 -23.602 1.00 0.00 <br />
ATOM 247 CA LYS A 34 -18.790 2.760 -23.629 1.00 0.00 <br />
ATOM 248 C LYS A 34 -19.330 2.102 -22.363 1.00 0.00 <br />
ATOM 249 O LYS A 34 -18.587 1.494 -21.588 1.00 0.00 <br />
ATOM 250 CB LYS A 34 -19.135 1.859 -24.817 1.00 0.00 <br />
ATOM 251 CG LYS A 34 -18.413 0.520 -24.789 1.00 0.00 <br />
ATOM 252 CD LYS A 34 -19.064 -0.505 -25.711 1.00 0.00 <br />
ATOM 253 CE LYS A 34 -20.442 -0.915 -25.197 1.00 0.00 <br />
ATOM 254 NZ LYS A 34 -21.063 -1.980 -26.035 1.00 0.00 <br />
ATOM 255 N LYS A 35 -20.638 2.228 -22.169 1.00 0.00 <br />
ATOM 256 CA LYS A 35 -21.311 1.609 -21.037 1.00 0.00 <br />
ATOM 257 C LYS A 35 -21.391 0.141 -21.441 1.00 0.00 <br />
ATOM 258 O LYS A 35 -21.684 -0.160 -22.597 1.00 0.00 <br />
ATOM 259 CB LYS A 35 -22.716 2.190 -20.873 1.00 0.00 <br />
ATOM 260 CG LYS A 35 -22.736 3.676 -20.514 1.00 0.00 <br />
ATOM 261 CD LYS A 35 -24.154 4.236 -20.479 1.00 0.00 <br />
ATOM 262 CE LYS A 35 -24.787 4.206 -21.868 1.00 0.00 <br />
ATOM 263 NZ LYS A 35 -26.128 4.854 -21.908 1.00 0.00 <br />
ATOM 264 N PHE A 36 -21.128 -0.769 -20.510 1.00 0.00 <br />
ATOM 265 CA PHE A 36 -21.158 -2.189 -20.842 1.00 0.00 <br />
ATOM 266 C PHE A 36 -22.232 -2.976 -20.104 1.00 0.00 <br />
ATOM 267 O PHE A 36 -22.508 -4.124 -20.445 1.00 0.00 <br />
ATOM 268 CB PHE A 36 -19.777 -2.815 -20.593 1.00 0.00 <br />
ATOM 269 CG PHE A 36 -19.232 -2.572 -19.209 1.00 0.00 <br />
ATOM 270 CD1 PHE A 36 -19.712 -3.287 -18.118 1.00 0.00 <br />
ATOM 271 CD2 PHE A 36 -18.236 -1.618 -18.999 1.00 0.00 <br />
ATOM 272 CE1 PHE A 36 -19.205 -3.056 -16.834 1.00 0.00 <br />
ATOM 273 CE2 PHE A 36 -17.726 -1.380 -17.724 1.00 0.00 <br />
ATOM 274 CZ PHE A 36 -18.213 -2.103 -16.640 1.00 0.00 <br />
ATOM 275 N ASP A 37 -22.847 -2.363 -19.099 1.00 0.00 <br />
ATOM 276 CA ASP A 37 -23.888 -3.052 -18.350 1.00 0.00 <br />
ATOM 277 C ASP A 37 -24.728 -2.064 -17.552 1.00 0.00 <br />
ATOM 278 O ASP A 37 -24.242 -1.013 -17.128 1.00 0.00 <br />
ATOM 279 CB ASP A 37 -23.264 -4.088 -17.408 1.00 0.00 <br />
ATOM 280 CG ASP A 37 -24.275 -5.107 -16.911 1.00 0.00 <br />
ATOM 281 OD1 ASP A 37 -25.448 -5.030 -17.330 1.00 0.00 <br />
ATOM 282 OD2 ASP A 37 -23.902 -5.987 -16.110 1.00 0.00 <br />
ATOM 283 N SER A 38 -25.997 -2.404 -17.358 1.00 0.00 <br />
ATOM 284 CA SER A 38 -26.901 -1.548 -16.603 1.00 0.00 <br />
ATOM 285 C SER A 38 -28.049 -2.351 -16.013 1.00 0.00 <br />
ATOM 286 O SER A 38 -28.886 -2.886 -16.743 1.00 0.00 <br />
ATOM 287 CB SER A 38 -27.462 -0.441 -17.503 1.00 0.00 <br />
ATOM 288 OG SER A 38 -28.493 0.280 -16.846 1.00 0.00 <br />
ATOM 289 N SER A 39 -28.078 -2.442 -14.687 1.00 0.00 <br />
ATOM 290 CA SER A 39 -29.145 -3.159 -14.003 1.00 0.00 <br />
ATOM 291 C SER A 39 -30.408 -2.309 -14.118 1.00 0.00 <br />
ATOM 292 O SER A 39 -31.523 -2.822 -14.055 1.00 0.00 <br />
ATOM 293 CB SER A 39 -28.796 -3.363 -12.525 1.00 0.00 <br />
ATOM 294 OG SER A 39 -28.735 -2.119 -11.842 1.00 0.00 <br />
ATOM 295 N ARG A 40 -30.220 -1.003 -14.289 1.00 0.00 <br />
ATOM 296 CA ARG A 40 -31.340 -0.074 -14.416 1.00 0.00 <br />
ATOM 297 C ARG A 40 -32.046 -0.233 -15.762 1.00 0.00 <br />
ATOM 298 O ARG A 40 -33.268 -0.120 -15.839 1.00 0.00 <br />
ATOM 299 CB ARG A 40 -30.860 1.376 -14.262 1.00 0.00 <br />
ATOM 300 CG ARG A 40 -30.171 1.692 -12.932 1.00 0.00 <br />
ATOM 301 CD ARG A 40 -29.980 3.199 -12.746 1.00 0.00 <br />
ATOM 302 NE ARG A 40 -29.299 3.527 -11.494 1.00 0.00 <br />
ATOM 303 CZ ARG A 40 -27.977 3.548 -11.339 1.00 0.00 <br />
ATOM 304 NH1 ARG A 40 -27.178 3.265 -12.361 1.00 0.00 <br />
ATOM 305 NH2 ARG A 40 -27.449 3.841 -10.153 1.00 0.00 <br />
ATOM 306 N ASP A 41 -31.276 -0.491 -16.818 1.00 0.00 <br />
ATOM 307 CA ASP A 41 -31.847 -0.660 -18.154 1.00 0.00 <br />
ATOM 308 C ASP A 41 -32.739 -1.890 -18.276 1.00 0.00 <br />
ATOM 309 O ASP A 41 -33.630 -1.937 -19.128 1.00 0.00 <br />
ATOM 310 CB ASP A 41 -30.746 -0.731 -19.217 1.00 0.00 <br />
ATOM 311 CG ASP A 41 -30.151 0.634 -19.535 1.00 0.00 <br />
ATOM 312 OD1 ASP A 41 -30.877 1.647 -19.413 1.00 0.00 <br />
ATOM 313 OD2 ASP A 41 -28.964 0.691 -19.925 1.00 0.00 <br />
ATOM 314 N ARG A 42 -32.489 -2.895 -17.444 1.00 0.00 <br />
ATOM 315 CA ARG A 42 -33.302 -4.107 -17.468 1.00 0.00 <br />
ATOM 316 C ARG A 42 -34.241 -4.125 -16.269 1.00 0.00 <br />
ATOM 317 O ARG A 42 -34.891 -5.134 -15.990 1.00 0.00 <br />
ATOM 318 CB ARG A 42 -32.417 -5.356 -17.459 1.00 0.00 <br />
ATOM 319 CG ARG A 42 -31.297 -5.319 -16.444 1.00 0.00 <br />
ATOM 320 CD ARG A 42 -30.666 -6.691 -16.265 1.00 0.00 <br />
ATOM 321 NE ARG A 42 -29.464 -6.621 -15.438 1.00 0.00 <br />
ATOM 322 CZ ARG A 42 -28.287 -6.179 -15.867 1.00 0.00 <br />
ATOM 323 NH1 ARG A 42 -28.146 -5.769 -17.122 1.00 0.00 <br />
ATOM 324 NH2 ARG A 42 -27.250 -6.139 -15.040 1.00 0.00 <br />
ATOM 325 N ASN A 43 -34.319 -2.988 -15.579 1.00 0.00 <br />
ATOM 326 CA ASN A 43 -35.175 -2.829 -14.406 1.00 0.00 <br />
ATOM 327 C ASN A 43 -35.087 -4.044 -13.488 1.00 0.00 <br />
ATOM 328 O ASN A 43 -36.086 -4.718 -13.240 1.00 0.00 <br />
ATOM 329 CB ASN A 43 -36.634 -2.621 -14.832 1.00 0.00 <br />
ATOM 330 CG ASN A 43 -36.826 -1.385 -15.700 1.00 0.00 <br />
ATOM 331 OD1 ASN A 43 -36.462 -1.371 -16.879 1.00 0.00 <br />
ATOM 332 ND2 ASN A 43 -37.400 -0.339 -15.115 1.00 0.00 <br />
ATOM 333 N LYS A 44 -33.893 -4.322 -12.982 1.00 0.00 <br />
ATOM 334 CA LYS A 44 -33.703 -5.468 -12.103 1.00 0.00 <br />
ATOM 335 C LYS A 44 -32.517 -5.268 -11.166 1.00 0.00 <br />
ATOM 336 O LYS A 44 -31.362 -5.377 -11.579 1.00 0.00 <br />
ATOM 337 CB LYS A 44 -33.500 -6.736 -12.942 1.00 0.00 <br />
ATOM 338 CG LYS A 44 -33.408 -8.027 -12.139 1.00 0.00 <br />
ATOM 339 CD LYS A 44 -33.426 -9.243 -13.063 1.00 0.00 <br />
ATOM 340 CE LYS A 44 -33.317 -10.554 -12.291 1.00 0.00 <br />
ATOM 341 NZ LYS A 44 -31.978 -10.744 -11.666 1.00 0.00 <br />
ATOM 342 N PRO A 45 -32.793 -4.960 -9.888 1.00 0.00 <br />
ATOM 343 CA PRO A 45 -31.738 -4.748 -8.893 1.00 0.00 <br />
ATOM 344 C PRO A 45 -30.772 -5.928 -8.838 1.00 0.00 <br />
ATOM 345 O PRO A 45 -31.162 -7.077 -9.061 1.00 0.00 <br />
ATOM 346 CB PRO A 45 -32.522 -4.579 -7.598 1.00 0.00 <br />
ATOM 347 CG PRO A 45 -33.763 -3.883 -8.066 1.00 0.00 <br />
ATOM 348 CD PRO A 45 -34.118 -4.669 -9.310 1.00 0.00 <br />
ATOM 349 N PHE A 46 -29.514 -5.626 -8.539 1.00 0.00 <br />
ATOM 350 CA PHE A 46 -28.450 -6.619 -8.448 1.00 0.00 <br />
ATOM 351 C PHE A 46 -28.140 -6.901 -6.973 1.00 0.00 <br />
ATOM 352 O PHE A 46 -28.031 -5.971 -6.170 1.00 0.00 <br />
ATOM 353 CB PHE A 46 -27.201 -6.068 -9.142 1.00 0.00 <br />
ATOM 354 CG PHE A 46 -26.012 -6.979 -9.083 1.00 0.00 <br />
ATOM 355 CD1 PHE A 46 -25.932 -8.098 -9.908 1.00 0.00 <br />
ATOM 356 CD2 PHE A 46 -24.952 -6.703 -8.220 1.00 0.00 <br />
ATOM 357 CE1 PHE A 46 -24.806 -8.931 -9.877 1.00 0.00 <br />
ATOM 358 CE2 PHE A 46 -23.823 -7.527 -8.179 1.00 0.00 <br />
ATOM 359 CZ PHE A 46 -23.747 -8.641 -9.008 1.00 0.00 <br />
ATOM 360 N LYS A 47 -27.997 -8.174 -6.618 1.00 0.00 <br />
ATOM 361 CA LYS A 47 -27.697 -8.540 -5.235 1.00 0.00 <br />
ATOM 362 C LYS A 47 -26.396 -9.325 -5.123 1.00 0.00 <br />
ATOM 363 O LYS A 47 -26.051 -10.107 -6.012 1.00 0.00 <br />
ATOM 364 CB LYS A 47 -28.832 -9.389 -4.641 1.00 0.00 <br />
ATOM 365 CG LYS A 47 -30.208 -8.726 -4.643 1.00 0.00 <br />
ATOM 366 CD LYS A 47 -31.244 -9.609 -3.937 1.00 0.00 <br />
ATOM 367 CE LYS A 47 -32.640 -9.011 -4.018 1.00 0.00 <br />
ATOM 368 NZ LYS A 47 -33.644 -9.817 -3.269 1.00 0.00 <br />
ATOM 369 N PHE A 48 -25.672 -9.108 -4.031 1.00 0.00 <br />
ATOM 370 CA PHE A 48 -24.429 -9.829 -3.781 1.00 0.00 <br />
ATOM 371 C PHE A 48 -24.117 -9.793 -2.295 1.00 0.00 <br />
ATOM 372 O PHE A 48 -24.493 -8.851 -1.596 1.00 0.00 <br />
ATOM 373 CB PHE A 48 -23.255 -9.237 -4.575 1.00 0.00 <br />
ATOM 374 CG PHE A 48 -22.809 -7.880 -4.098 1.00 0.00 <br />
ATOM 375 CD1 PHE A 48 -23.532 -6.738 -4.423 1.00 0.00 <br />
ATOM 376 CD2 PHE A 48 -21.653 -7.745 -3.334 1.00 0.00 <br />
ATOM 377 CE1 PHE A 48 -23.105 -5.470 -3.995 1.00 0.00 <br />
ATOM 378 CE2 PHE A 48 -21.218 -6.489 -2.900 1.00 0.00 <br />
ATOM 379 CZ PHE A 48 -21.947 -5.350 -3.233 1.00 0.00 <br />
ATOM 380 N ARG A 49 -23.429 -10.829 -1.825 1.00 0.00 <br />
ATOM 381 CA ARG A 49 -23.059 -10.968 -0.418 1.00 0.00 <br />
ATOM 382 C ARG A 49 -21.734 -10.287 -0.090 1.00 0.00 <br />
ATOM 383 O ARG A 49 -20.716 -10.525 -0.748 1.00 0.00 <br />
ATOM 384 CB ARG A 49 -22.951 -12.452 -0.058 1.00 0.00 <br />
ATOM 385 CG ARG A 49 -24.171 -13.286 -0.420 1.00 0.00 <br />
ATOM 386 CD ARG A 49 -23.766 -14.719 -0.764 1.00 0.00 <br />
ATOM 387 NE ARG A 49 -23.007 -15.364 0.306 1.00 0.00 <br />
ATOM 388 CZ ARG A 49 -22.374 -16.527 0.179 1.00 0.00 <br />
ATOM 389 NH1 ARG A 49 -22.404 -17.182 -0.975 1.00 0.00 <br />
ATOM 390 NH2 ARG A 49 -21.708 -17.040 1.206 1.00 0.00 <br />
ATOM 391 N ILE A 50 -21.755 -9.451 0.942 1.00 0.00 <br />
ATOM 392 CA ILE A 50 -20.566 -8.739 1.395 1.00 0.00 <br />
ATOM 393 C ILE A 50 -19.517 -9.697 1.954 1.00 0.00 <br />
ATOM 394 O ILE A 50 -19.832 -10.568 2.758 1.00 0.00 <br />
ATOM 395 CB ILE A 50 -20.925 -7.719 2.508 1.00 0.00 <br />
ATOM 396 CG1 ILE A 50 -21.499 -6.444 1.886 1.00 0.00 <br />
ATOM 397 CG2 ILE A 50 -19.697 -7.414 3.361 1.00 0.00 <br />
ATOM 398 CD1 ILE A 50 -20.498 -5.673 1.043 1.00 0.00 <br />
ATOM 399 N GLY A 51 -18.272 -9.530 1.522 1.00 0.00 <br />
ATOM 400 CA GLY A 51 -17.189 -10.361 2.021 1.00 0.00 <br />
ATOM 401 C GLY A 51 -17.100 -11.785 1.506 1.00 0.00 <br />
ATOM 402 O GLY A 51 -16.335 -12.591 2.044 1.00 0.00 <br />
ATOM 403 N LYS A 52 -17.870 -12.107 0.472 1.00 0.00 <br />
ATOM 404 CA LYS A 52 -17.849 -13.452 -0.086 1.00 0.00 <br />
ATOM 405 C LYS A 52 -17.088 -13.521 -1.405 1.00 0.00 <br />
ATOM 406 O LYS A 52 -17.124 -14.539 -2.097 1.00 0.00 <br />
ATOM 407 CB LYS A 52 -19.277 -13.965 -0.282 1.00 0.00 <br />
ATOM 408 CG LYS A 52 -20.037 -14.182 1.018 1.00 0.00 <br />
ATOM 409 CD LYS A 52 -19.334 -15.209 1.898 1.00 0.00 <br />
ATOM 410 CE LYS A 52 -20.107 -15.474 3.179 1.00 0.00 <br />
ATOM 411 NZ LYS A 52 -19.443 -16.511 4.020 1.00 0.00 <br />
ATOM 412 N GLN A 53 -16.403 -12.435 -1.749 1.00 0.00 <br />
ATOM 413 CA GLN A 53 -15.627 -12.380 -2.984 1.00 0.00 <br />
ATOM 414 C GLN A 53 -16.453 -12.745 -4.212 1.00 0.00 <br />
ATOM 415 O GLN A 53 -15.972 -13.447 -5.103 1.00 0.00 <br />
ATOM 416 CB GLN A 53 -14.432 -13.326 -2.889 1.00 0.00 <br />
ATOM 417 CG GLN A 53 -13.499 -13.013 -1.738 1.00 0.00 <br />
ATOM 418 CD GLN A 53 -12.503 -14.119 -1.491 1.00 0.00 <br />
ATOM 419 OE1 GLN A 53 -12.881 -15.255 -1.200 1.00 0.00 <br />
ATOM 420 NE2 GLN A 53 -11.219 -13.796 -1.602 1.00 0.00 <br />
ATOM 421 N GLU A 54 -17.692 -12.271 -4.268 1.00 0.00 <br />
ATOM 422 CA GLU A 54 -18.543 -12.569 -5.416 1.00 0.00 <br />
ATOM 423 C GLU A 54 -18.362 -11.547 -6.533 1.00 0.00 <br />
ATOM 424 O GLU A 54 -18.608 -11.846 -7.702 1.00 0.00 <br />
ATOM 425 CB GLU A 54 -20.012 -12.595 -4.999 1.00 0.00 <br />
ATOM 426 CG GLU A 54 -20.307 -13.506 -3.826 1.00 0.00 <br />
ATOM 427 CD GLU A 54 -21.785 -13.651 -3.582 1.00 0.00 <br />
ATOM 428 OE1 GLU A 54 -22.499 -12.628 -3.654 1.00 0.00 <br />
ATOM 429 OE2 GLU A 54 -22.232 -14.786 -3.313 1.00 0.00 <br />
ATOM 430 N VAL A 55 -17.933 -10.341 -6.172 1.00 0.00 <br />
ATOM 431 CA VAL A 55 -17.741 -9.276 -7.152 1.00 0.00 <br />
ATOM 432 C VAL A 55 -16.340 -8.677 -7.046 1.00 0.00 <br />
ATOM 433 O VAL A 55 -15.673 -8.827 -6.022 1.00 0.00 <br />
ATOM 434 CB VAL A 55 -18.788 -8.160 -6.951 1.00 0.00 <br />
ATOM 435 CG1 VAL A 55 -20.200 -8.755 -7.006 1.00 0.00 <br />
ATOM 436 CG2 VAL A 55 -18.560 -7.464 -5.613 1.00 0.00 <br />
ATOM 437 N ILE A 56 -15.894 -7.999 -8.100 1.00 0.00 <br />
ATOM 438 CA ILE A 56 -14.564 -7.394 -8.092 1.00 0.00 <br />
ATOM 439 C ILE A 56 -14.374 -6.523 -6.853 1.00 0.00 <br />
ATOM 440 O ILE A 56 -15.321 -5.901 -6.371 1.00 0.00 <br />
ATOM 441 CB ILE A 56 -14.307 -6.554 -9.375 1.00 0.00 <br />
ATOM 442 CG1 ILE A 56 -15.440 -5.551 -9.602 1.00 0.00 <br />
ATOM 443 CG2 ILE A 56 -14.182 -7.488 -10.575 1.00 0.00 <br />
ATOM 444 CD1 ILE A 56 -15.210 -4.630 -10.793 1.00 0.00 <br />
ATOM 445 N LYS A 57 -13.144 -6.485 -6.345 1.00 0.00 <br />
ATOM 446 CA LYS A 57 -12.824 -5.723 -5.138 1.00 0.00 <br />
ATOM 447 C LYS A 57 -13.315 -4.287 -5.109 1.00 0.00 <br />
ATOM 448 O LYS A 57 -13.879 -3.841 -4.111 1.00 0.00 <br />
ATOM 449 CB LYS A 57 -11.313 -5.731 -4.885 1.00 0.00 <br />
ATOM 450 CG LYS A 57 -10.787 -7.039 -4.334 1.00 0.00 <br />
ATOM 451 CD LYS A 57 -9.324 -6.910 -3.923 1.00 0.00 <br />
ATOM 452 CE LYS A 57 -8.825 -8.180 -3.246 1.00 0.00 <br />
ATOM 453 NZ LYS A 57 -7.395 -8.065 -2.826 1.00 0.00 <br />
ATOM 454 N GLY A 58 -13.080 -3.562 -6.199 1.00 0.00 <br />
ATOM 455 CA GLY A 58 -13.492 -2.175 -6.264 1.00 0.00 <br />
ATOM 456 C GLY A 58 -14.979 -1.931 -6.085 1.00 0.00 <br />
ATOM 457 O GLY A 58 -15.385 -0.942 -5.471 1.00 0.00 <br />
ATOM 458 N PHE A 59 -15.797 -2.826 -6.624 1.00 0.00 <br />
ATOM 459 CA PHE A 59 -17.242 -2.687 -6.527 1.00 0.00 <br />
ATOM 460 C PHE A 59 -17.673 -2.948 -5.086 1.00 0.00 <br />
ATOM 461 O PHE A 59 -18.462 -2.191 -4.519 1.00 0.00 <br />
ATOM 462 CB PHE A 59 -17.915 -3.664 -7.498 1.00 0.00 <br />
ATOM 463 CG PHE A 59 -19.390 -3.413 -7.703 1.00 0.00 <br />
ATOM 464 CD1 PHE A 59 -20.328 -3.891 -6.788 1.00 0.00 <br />
ATOM 465 CD2 PHE A 59 -19.840 -2.725 -8.828 1.00 0.00 <br />
ATOM 466 CE1 PHE A 59 -21.693 -3.692 -6.990 1.00 0.00 <br />
ATOM 467 CE2 PHE A 59 -21.204 -2.517 -9.044 1.00 0.00 <br />
ATOM 468 CZ PHE A 59 -22.136 -3.003 -8.123 1.00 0.00 <br />
ATOM 469 N GLU A 60 -17.132 -4.001 -4.482 1.00 0.00 <br />
ATOM 470 CA GLU A 60 -17.483 -4.323 -3.105 1.00 0.00 <br />
ATOM 471 C GLU A 60 -16.952 -3.283 -2.119 1.00 0.00 <br />
ATOM 472 O GLU A 60 -17.652 -2.894 -1.191 1.00 0.00 <br />
ATOM 473 CB GLU A 60 -16.958 -5.706 -2.707 1.00 0.00 <br />
ATOM 474 CG GLU A 60 -17.614 -6.211 -1.425 1.00 0.00 <br />
ATOM 475 CD GLU A 60 -17.145 -7.584 -1.006 1.00 0.00 <br />
ATOM 476 OE1 GLU A 60 -16.906 -8.432 -1.892 1.00 0.00 <br />
ATOM 477 OE2 GLU A 60 -17.035 -7.820 0.218 1.00 0.00 <br />
ATOM 478 N GLU A 61 -15.713 -2.837 -2.311 1.00 0.00 <br />
ATOM 479 CA GLU A 61 -15.147 -1.839 -1.410 1.00 0.00 <br />
ATOM 480 C GLU A 61 -15.923 -0.531 -1.516 1.00 0.00 <br />
ATOM 481 O GLU A 61 -16.061 0.204 -0.537 1.00 0.00 <br />
ATOM 482 CB GLU A 61 -13.669 -1.603 -1.728 1.00 0.00 <br />
ATOM 483 CG GLU A 61 -12.814 -2.848 -1.570 1.00 0.00 <br />
ATOM 484 CD GLU A 61 -11.345 -2.583 -1.813 1.00 0.00 <br />
ATOM 485 OE1 GLU A 61 -11.027 -1.644 -2.575 1.00 0.00 <br />
ATOM 486 OE2 GLU A 61 -10.510 -3.324 -1.255 1.00 0.00 <br />
ATOM 487 N GLY A 62 -16.429 -0.240 -2.709 1.00 0.00 <br />
ATOM 488 CA GLY A 62 -17.199 0.974 -2.888 1.00 0.00 <br />
ATOM 489 C GLY A 62 -18.501 0.877 -2.109 1.00 0.00 <br />
ATOM 490 O GLY A 62 -18.852 1.769 -1.333 1.00 0.00 <br />
ATOM 491 N ALA A 63 -19.212 -0.228 -2.306 1.00 0.00 <br />
ATOM 492 CA ALA A 63 -20.487 -0.447 -1.635 1.00 0.00 <br />
ATOM 493 C ALA A 63 -20.334 -0.496 -0.123 1.00 0.00 <br />
ATOM 494 O ALA A 63 -21.180 0.016 0.615 1.00 0.00 <br />
ATOM 495 CB ALA A 63 -21.115 -1.742 -2.131 1.00 0.00 <br />
ATOM 496 N ALA A 64 -19.252 -1.118 0.337 1.00 0.00 <br />
ATOM 497 CA ALA A 64 -19.001 -1.252 1.764 1.00 0.00 <br />
ATOM 498 C ALA A 64 -18.902 0.092 2.481 1.00 0.00 <br />
ATOM 499 O ALA A 64 -19.242 0.190 3.661 1.00 0.00 <br />
ATOM 500 CB ALA A 64 -17.731 -2.069 1.996 1.00 0.00 <br />
ATOM 501 N GLN A 65 -18.452 1.129 1.779 1.00 0.00 <br />
ATOM 502 CA GLN A 65 -18.321 2.444 2.408 1.00 0.00 <br />
ATOM 503 C GLN A 65 -19.489 3.386 2.132 1.00 0.00 <br />
ATOM 504 O GLN A 65 -19.404 4.588 2.396 1.00 0.00 <br />
ATOM 505 CB GLN A 65 -17.011 3.111 1.981 1.00 0.00 <br />
ATOM 506 CG GLN A 65 -16.896 3.386 0.498 1.00 0.00 <br />
ATOM 507 CD GLN A 65 -15.542 3.956 0.135 1.00 0.00 <br />
ATOM 508 OE1 GLN A 65 -15.246 5.122 0.416 1.00 0.00 <br />
ATOM 509 NE2 GLN A 65 -14.705 3.135 -0.473 1.00 0.00 <br />
ATOM 510 N MET A 66 -20.574 2.837 1.599 1.00 0.00 <br />
ATOM 511 CA MET A 66 -21.769 3.621 1.297 1.00 0.00 <br />
ATOM 512 C MET A 66 -22.858 3.312 2.322 1.00 0.00 <br />
ATOM 513 O MET A 66 -22.951 2.186 2.809 1.00 0.00 <br />
ATOM 514 CB MET A 66 -22.278 3.286 -0.107 1.00 0.00 <br />
ATOM 515 CG MET A 66 -21.360 3.779 -1.227 1.00 0.00 <br />
ATOM 516 SD MET A 66 -21.802 3.102 -2.840 1.00 0.00 <br />
ATOM 517 CE MET A 66 -23.385 3.919 -3.121 1.00 0.00 <br />
ATOM 518 N SER A 67 -23.673 4.307 2.655 1.00 0.00 <br />
ATOM 519 CA SER A 67 -24.753 4.094 3.613 1.00 0.00 <br />
ATOM 520 C SER A 67 -26.065 3.852 2.864 1.00 0.00 <br />
ATOM 521 O SER A 67 -26.175 4.150 1.668 1.00 0.00 <br />
ATOM 522 CB SER A 67 -24.879 5.289 4.574 1.00 0.00 <br />
ATOM 523 OG SER A 67 -25.060 6.519 3.893 1.00 0.00 <br />
ATOM 524 N LEU A 68 -27.052 3.300 3.565 1.00 0.00 <br />
ATOM 525 CA LEU A 68 -28.343 2.990 2.959 1.00 0.00 <br />
ATOM 526 C LEU A 68 -28.934 4.161 2.183 1.00 0.00 <br />
ATOM 527 O LEU A 68 -29.022 5.274 2.697 1.00 0.00 <br />
ATOM 528 CB LEU A 68 -29.337 2.534 4.033 1.00 0.00 <br />
ATOM 529 CG LEU A 68 -30.677 2.004 3.514 1.00 0.00 <br />
ATOM 530 CD1 LEU A 68 -30.438 0.840 2.560 1.00 0.00 <br />
ATOM 531 CD2 LEU A 68 -31.539 1.556 4.689 1.00 0.00 <br />
ATOM 532 N GLY A 69 -29.331 3.896 0.940 1.00 0.00 <br />
ATOM 533 CA GLY A 69 -29.915 4.928 0.094 1.00 0.00 <br />
ATOM 534 C GLY A 69 -28.910 5.768 -0.678 1.00 0.00 <br />
ATOM 535 O GLY A 69 -29.282 6.535 -1.569 1.00 0.00 <br />
ATOM 536 N GLN A 70 -27.629 5.632 -0.348 1.00 0.00 <br />
ATOM 537 CA GLN A 70 -26.611 6.413 -1.033 1.00 0.00 <br />
ATOM 538 C GLN A 70 -26.414 5.947 -2.464 1.00 0.00 <br />
ATOM 539 O GLN A 70 -26.568 4.764 -2.770 1.00 0.00 <br />
ATOM 540 CB GLN A 70 -25.268 6.322 -0.299 1.00 0.00 <br />
ATOM 541 CG GLN A 70 -24.212 7.269 -0.843 1.00 0.00 <br />
ATOM 542 CD GLN A 70 -22.892 7.173 -0.083 1.00 0.00 <br />
ATOM 543 OE1 GLN A 70 -22.825 6.580 0.993 1.00 0.00 <br />
ATOM 544 NE2 GLN A 70 -21.841 7.771 -0.640 1.00 0.00 <br />
ATOM 545 N ARG A 71 -26.081 6.899 -3.334 1.00 0.00 <br />
ATOM 546 CA ARG A 71 -25.802 6.632 -4.739 1.00 0.00 <br />
ATOM 547 C ARG A 71 -24.497 7.348 -5.030 1.00 0.00 <br />
ATOM 548 O ARG A 71 -24.319 8.513 -4.659 1.00 0.00 <br />
ATOM 549 CB ARG A 71 -26.902 7.190 -5.646 1.00 0.00 <br />
ATOM 550 CG ARG A 71 -26.590 7.038 -7.127 1.00 0.00 <br />
ATOM 551 CD ARG A 71 -27.729 7.569 -7.984 1.00 0.00 <br />
ATOM 552 NE ARG A 71 -27.481 7.406 -9.413 1.00 0.00 <br />
ATOM 553 CZ ARG A 71 -28.266 7.914 -10.361 1.00 0.00 <br />
ATOM 554 NH1 ARG A 71 -29.343 8.617 -10.021 1.00 0.00 <br />
ATOM 555 NH2 ARG A 71 -27.983 7.719 -11.644 1.00 0.00 <br />
ATOM 556 N ALA A 72 -23.575 6.664 -5.692 1.00 0.00 <br />
ATOM 557 CA ALA A 72 -22.300 7.284 -5.968 1.00 0.00 <br />
ATOM 558 C ALA A 72 -21.643 6.762 -7.226 1.00 0.00 <br />
ATOM 559 O ALA A 72 -21.975 5.689 -7.726 1.00 0.00 <br />
ATOM 560 CB ALA A 72 -21.367 7.083 -4.781 1.00 0.00 <br />
ATOM 561 N LYS A 73 -20.706 7.552 -7.728 1.00 0.00 <br />
ATOM 562 CA LYS A 73 -19.935 7.202 -8.907 1.00 0.00 <br />
ATOM 563 C LYS A 73 -18.658 6.549 -8.385 1.00 0.00 <br />
ATOM 564 O LYS A 73 -17.917 7.162 -7.608 1.00 0.00 <br />
ATOM 565 CB LYS A 73 -19.588 8.471 -9.689 1.00 0.00 <br />
ATOM 566 CG LYS A 73 -18.573 8.289 -10.805 1.00 0.00 <br />
ATOM 567 CD LYS A 73 -18.169 9.649 -11.368 1.00 0.00 <br />
ATOM 568 CE LYS A 73 -17.260 9.522 -12.575 1.00 0.00 <br />
ATOM 569 NZ LYS A 73 -16.030 8.757 -12.253 1.00 0.00 <br />
ATOM 570 N LEU A 74 -18.405 5.303 -8.780 1.00 0.00 <br />
ATOM 571 CA LEU A 74 -17.196 4.628 -8.326 1.00 0.00 <br />
ATOM 572 C LEU A 74 -16.200 4.546 -9.470 1.00 0.00 <br />
ATOM 573 O LEU A 74 -16.546 4.130 -10.578 1.00 0.00 <br />
ATOM 574 CB LEU A 74 -17.487 3.201 -7.844 1.00 0.00 <br />
ATOM 575 CG LEU A 74 -18.759 2.834 -7.078 1.00 0.00 <br />
ATOM 576 CD1 LEU A 74 -18.576 1.442 -6.495 1.00 0.00 <br />
ATOM 577 CD2 LEU A 74 -19.045 3.828 -5.981 1.00 0.00 <br />
ATOM 578 N THR A 75 -14.967 4.958 -9.209 1.00 0.00 <br />
ATOM 579 CA THR A 75 -13.935 4.865 -10.222 1.00 0.00 <br />
ATOM 580 C THR A 75 -12.982 3.799 -9.704 1.00 0.00 <br />
ATOM 581 O THR A 75 -12.352 3.969 -8.658 1.00 0.00 <br />
ATOM 582 CB THR A 75 -13.196 6.197 -10.409 1.00 0.00 <br />
ATOM 583 OG1 THR A 75 -14.144 7.221 -10.746 1.00 0.00 <br />
ATOM 584 CG2 THR A 75 -12.171 6.078 -11.536 1.00 0.00 <br />
ATOM 585 N CYS A 76 -12.897 2.695 -10.437 1.00 0.00 <br />
ATOM 586 CA CYS A 76 -12.063 1.569 -10.044 1.00 0.00 <br />
ATOM 587 C CYS A 76 -10.873 1.349 -10.972 1.00 0.00 <br />
ATOM 588 O CYS A 76 -11.045 1.139 -12.174 1.00 0.00 <br />
ATOM 589 CB CYS A 76 -12.909 0.292 -10.016 1.00 0.00 <br />
ATOM 590 SG CYS A 76 -14.468 0.417 -9.079 1.00 0.00 <br />
ATOM 591 N THR A 77 -9.669 1.395 -10.411 1.00 0.00 <br />
ATOM 592 CA THR A 77 -8.467 1.159 -11.203 1.00 0.00 <br />
ATOM 593 C THR A 77 -8.425 -0.340 -11.518 1.00 0.00 <br />
ATOM 594 O THR A 77 -9.075 -1.147 -10.845 1.00 0.00 <br />
ATOM 595 CB THR A 77 -7.188 1.575 -10.434 1.00 0.00 <br />
ATOM 596 OG1 THR A 77 -7.215 1.014 -9.116 1.00 0.00 <br />
ATOM 597 CG2 THR A 77 -7.096 3.094 -10.336 1.00 0.00 <br />
ATOM 598 N PRO A 78 -7.664 -0.731 -12.551 1.00 0.00 <br />
ATOM 599 CA PRO A 78 -7.550 -2.137 -12.953 1.00 0.00 <br />
ATOM 600 C PRO A 78 -7.252 -3.129 -11.823 1.00 0.00 <br />
ATOM 601 O PRO A 78 -7.852 -4.205 -11.765 1.00 0.00 <br />
ATOM 602 CB PRO A 78 -6.432 -2.110 -13.995 1.00 0.00 <br />
ATOM 603 CG PRO A 78 -6.552 -0.742 -14.588 1.00 0.00 <br />
ATOM 604 CD PRO A 78 -6.785 0.122 -13.373 1.00 0.00 <br />
ATOM 605 N ASP A 79 -6.335 -2.771 -10.926 1.00 0.00 <br />
ATOM 606 CA ASP A 79 -5.965 -3.672 -9.836 1.00 0.00 <br />
ATOM 607 C ASP A 79 -7.124 -4.062 -8.914 1.00 0.00 <br />
ATOM 608 O ASP A 79 -7.050 -5.081 -8.227 1.00 0.00 <br />
ATOM 609 CB ASP A 79 -4.814 -3.077 -9.015 1.00 0.00 <br />
ATOM 610 CG ASP A 79 -5.149 -1.726 -8.445 1.00 0.00 <br />
ATOM 611 OD1 ASP A 79 -5.459 -0.813 -9.233 1.00 0.00 <br />
ATOM 612 OD2 ASP A 79 -5.101 -1.574 -7.212 1.00 0.00 <br />
ATOM 613 N VAL A 80 -8.183 -3.254 -8.885 1.00 0.00 <br />
ATOM 614 CA VAL A 80 -9.349 -3.580 -8.067 1.00 0.00 <br />
ATOM 615 C VAL A 80 -10.546 -3.901 -8.971 1.00 0.00 <br />
ATOM 616 O VAL A 80 -11.698 -3.845 -8.544 1.00 0.00 <br />
ATOM 617 CB VAL A 80 -9.716 -2.432 -7.082 1.00 0.00 <br />
ATOM 618 CG1 VAL A 80 -8.655 -2.336 -5.979 1.00 0.00 <br />
ATOM 619 CG2 VAL A 80 -9.832 -1.108 -7.826 1.00 0.00 <br />
ATOM 620 N ALA A 81 -10.252 -4.235 -10.227 1.00 0.00 <br />
ATOM 621 CA ALA A 81 -11.277 -4.602 -11.196 1.00 0.00 <br />
ATOM 622 C ALA A 81 -10.854 -5.906 -11.884 1.00 0.00 <br />
ATOM 623 O ALA A 81 -10.777 -6.951 -11.233 1.00 0.00 <br />
ATOM 624 CB ALA A 81 -11.466 -3.486 -12.227 1.00 0.00 <br />
ATOM 625 N TYR A 82 -10.555 -5.848 -13.180 1.00 0.00 <br />
ATOM 626 CA TYR A 82 -10.157 -7.049 -13.914 1.00 0.00 <br />
ATOM 627 C TYR A 82 -8.664 -7.146 -14.248 1.00 0.00 <br />
ATOM 628 O TYR A 82 -8.232 -8.062 -14.952 1.00 0.00 <br />
ATOM 629 CB TYR A 82 -11.020 -7.178 -15.178 1.00 0.00 <br />
ATOM 630 CG TYR A 82 -12.484 -7.397 -14.844 1.00 0.00 <br />
ATOM 631 CD1 TYR A 82 -12.947 -8.650 -14.432 1.00 0.00 <br />
ATOM 632 CD2 TYR A 82 -13.393 -6.338 -14.870 1.00 0.00 <br />
ATOM 633 CE1 TYR A 82 -14.280 -8.841 -14.046 1.00 0.00 <br />
ATOM 634 CE2 TYR A 82 -14.730 -6.518 -14.490 1.00 0.00 <br />
ATOM 635 CZ TYR A 82 -15.162 -7.770 -14.076 1.00 0.00 <br />
ATOM 636 OH TYR A 82 -16.466 -7.938 -13.668 1.00 0.00 <br />
ATOM 637 N GLY A 83 -7.885 -6.198 -13.739 1.00 0.00 <br />
ATOM 638 CA GLY A 83 -6.445 -6.208 -13.944 1.00 0.00 <br />
ATOM 639 C GLY A 83 -5.895 -6.301 -15.357 1.00 0.00 <br />
ATOM 640 O GLY A 83 -6.486 -5.792 -16.307 1.00 0.00 <br />
ATOM 641 N ALA A 84 -4.746 -6.959 -15.486 1.00 0.00 <br />
ATOM 642 CA ALA A 84 -4.080 -7.109 -16.776 1.00 0.00 <br />
ATOM 643 C ALA A 84 -4.792 -8.114 -17.665 1.00 0.00 <br />
ATOM 644 O ALA A 84 -4.618 -8.108 -18.883 1.00 0.00 <br />
ATOM 645 CB ALA A 84 -2.636 -7.538 -16.568 1.00 0.00 <br />
ATOM 646 N THR A 85 -5.596 -8.971 -17.048 1.00 0.00 <br />
ATOM 647 CA THR A 85 -6.330 -9.998 -17.776 1.00 0.00 <br />
ATOM 648 C THR A 85 -7.594 -9.470 -18.440 1.00 0.00 <br />
ATOM 649 O THR A 85 -7.944 -9.903 -19.538 1.00 0.00 <br />
ATOM 650 CB THR A 85 -6.745 -11.156 -16.843 1.00 0.00 <br />
ATOM 651 OG1 THR A 85 -5.584 -11.705 -16.214 1.00 0.00 <br />
ATOM 652 CG2 THR A 85 -7.459 -12.252 -17.633 1.00 0.00 <br />
ATOM 653 N GLY A 86 -8.275 -8.542 -17.771 1.00 0.00 <br />
ATOM 654 CA GLY A 86 -9.514 -8.003 -18.301 1.00 0.00 <br />
ATOM 655 C GLY A 86 -10.593 -9.071 -18.186 1.00 0.00 <br />
ATOM 656 O GLY A 86 -10.348 -10.127 -17.610 1.00 0.00 <br />
ATOM 657 N HIS A 87 -11.787 -8.796 -18.704 1.00 0.00 <br />
ATOM 658 CA HIS A 87 -12.871 -9.776 -18.677 1.00 0.00 <br />
ATOM 659 C HIS A 87 -13.148 -10.182 -20.125 1.00 0.00 <br />
ATOM 660 O HIS A 87 -13.560 -9.354 -20.939 1.00 0.00 <br />
ATOM 661 CB HIS A 87 -14.139 -9.181 -18.057 1.00 0.00 <br />
ATOM 662 CG HIS A 87 -15.283 -10.143 -18.001 1.00 0.00 <br />
ATOM 663 ND1 HIS A 87 -15.322 -11.202 -17.118 1.00 0.00 <br />
ATOM 664 CD2 HIS A 87 -16.407 -10.233 -18.748 1.00 0.00 <br />
ATOM 665 CE1 HIS A 87 -16.424 -11.903 -17.324 1.00 0.00 <br />
ATOM 666 NE2 HIS A 87 -17.100 -11.337 -18.309 1.00 0.00 <br />
ATOM 667 N PRO A 88 -12.927 -11.464 -20.460 1.00 0.00 <br />
ATOM 668 CA PRO A 88 -13.140 -11.985 -21.813 1.00 0.00 <br />
ATOM 669 C PRO A 88 -14.260 -11.359 -22.632 1.00 0.00 <br />
ATOM 670 O PRO A 88 -15.435 -11.455 -22.277 1.00 0.00 <br />
ATOM 671 CB PRO A 88 -13.354 -13.476 -21.570 1.00 0.00 <br />
ATOM 672 CG PRO A 88 -12.350 -13.741 -20.477 1.00 0.00 <br />
ATOM 673 CD PRO A 88 -12.577 -12.558 -19.532 1.00 0.00 <br />
ATOM 674 N GLY A 89 -13.870 -10.708 -23.726 1.00 0.00 <br />
ATOM 675 CA GLY A 89 -14.820 -10.091 -24.638 1.00 0.00 <br />
ATOM 676 C GLY A 89 -15.633 -8.892 -24.181 1.00 0.00 <br />
ATOM 677 O GLY A 89 -16.491 -8.427 -24.926 1.00 0.00 <br />
ATOM 678 N VAL A 90 -15.378 -8.376 -22.982 1.00 0.00 <br />
ATOM 679 CA VAL A 90 -16.140 -7.228 -22.492 1.00 0.00 <br />
ATOM 680 C VAL A 90 -15.254 -6.116 -21.923 1.00 0.00 <br />
ATOM 681 O VAL A 90 -15.404 -4.945 -22.280 1.00 0.00 <br />
ATOM 682 CB VAL A 90 -17.147 -7.655 -21.395 1.00 0.00 <br />
ATOM 683 CG1 VAL A 90 -18.042 -6.484 -21.030 1.00 0.00 <br />
ATOM 684 CG2 VAL A 90 -17.979 -8.835 -21.881 1.00 0.00 <br />
ATOM 685 N ILE A 91 -14.338 -6.491 -21.034 1.00 0.00 <br />
ATOM 686 CA ILE A 91 -13.427 -5.533 -20.408 1.00 0.00 <br />
ATOM 687 C ILE A 91 -11.994 -5.844 -20.841 1.00 0.00 <br />
ATOM 688 O ILE A 91 -11.483 -6.937 -20.583 1.00 0.00 <br />
ATOM 689 CB ILE A 91 -13.467 -5.634 -18.864 1.00 0.00 <br />
ATOM 690 CG1 ILE A 91 -14.913 -5.540 -18.355 1.00 0.00 <br />
ATOM 691 CG2 ILE A 91 -12.562 -4.552 -18.250 1.00 0.00 <br />
ATOM 692 CD1 ILE A 91 -15.621 -4.225 -18.679 1.00 0.00 <br />
ATOM 693 N PRO A 92 -11.321 -4.886 -21.501 1.00 0.00 <br />
ATOM 694 CA PRO A 92 -9.941 -5.129 -21.936 1.00 0.00 <br />
ATOM 695 C PRO A 92 -8.929 -5.029 -20.802 1.00 0.00 <br />
ATOM 696 O PRO A 92 -9.249 -4.561 -19.706 1.00 0.00 <br />
ATOM 697 CB PRO A 92 -9.716 -4.042 -22.985 1.00 0.00 <br />
ATOM 698 CG PRO A 92 -10.539 -2.910 -22.458 1.00 0.00 <br />
ATOM 699 CD PRO A 92 -11.822 -3.607 -22.031 1.00 0.00 <br />
ATOM 700 N PRO A 93 -7.691 -5.487 -21.050 1.00 0.00 <br />
ATOM 701 CA PRO A 93 -6.636 -5.431 -20.038 1.00 0.00 <br />
ATOM 702 C PRO A 93 -6.411 -3.987 -19.571 1.00 0.00 <br />
ATOM 703 O PRO A 93 -6.597 -3.040 -20.345 1.00 0.00 <br />
ATOM 704 CB PRO A 93 -5.426 -5.984 -20.780 1.00 0.00 <br />
ATOM 705 CG PRO A 93 -6.045 -7.000 -21.701 1.00 0.00 <br />
ATOM 706 CD PRO A 93 -7.251 -6.261 -22.228 1.00 0.00 <br />
ATOM 707 N ASN A 94 -6.030 -3.837 -18.304 1.00 0.00 <br />
ATOM 708 CA ASN A 94 -5.740 -2.536 -17.692 1.00 0.00 <br />
ATOM 709 C ASN A 94 -6.852 -1.503 -17.804 1.00 0.00 <br />
ATOM 710 O ASN A 94 -6.586 -0.313 -17.988 1.00 0.00 <br />
ATOM 711 CB ASN A 94 -4.470 -1.934 -18.295 1.00 0.00 <br />
ATOM 712 CG ASN A 94 -3.777 -0.985 -17.335 1.00 0.00 <br />
ATOM 713 OD1 ASN A 94 -3.383 -1.387 -16.244 1.00 0.00 <br />
ATOM 714 ND2 ASN A 94 -3.630 0.271 -17.730 1.00 0.00 <br />
ATOM 715 N ALA A 95 -8.093 -1.941 -17.669 1.00 0.00 <br />
ATOM 716 CA ALA A 95 -9.198 -1.012 -17.786 1.00 0.00 <br />
ATOM 717 C ALA A 95 -9.671 -0.422 -16.469 1.00 0.00 <br />
ATOM 718 O ALA A 95 -9.956 -1.148 -15.512 1.00 0.00 <br />
ATOM 719 CB ALA A 95 -10.369 -1.684 -18.494 1.00 0.00 <br />
ATOM 720 N THR A 96 -9.736 0.904 -16.423 1.00 0.00 <br />
ATOM 721 CA THR A 96 -10.260 1.593 -15.252 1.00 0.00 <br />
ATOM 722 C THR A 96 -11.769 1.614 -15.502 1.00 0.00 <br />
ATOM 723 O THR A 96 -12.228 1.995 -16.589 1.00 0.00 <br />
ATOM 724 CB THR A 96 -9.700 3.031 -15.148 1.00 0.00 <br />
ATOM 725 OG1 THR A 96 -8.320 2.970 -14.751 1.00 0.00 <br />
ATOM 726 CG2 THR A 96 -10.492 3.849 -14.140 1.00 0.00 <br />
ATOM 727 N LEU A 97 -12.543 1.190 -14.510 1.00 0.00 <br />
ATOM 728 CA LEU A 97 -13.992 1.121 -14.674 1.00 0.00 <br />
ATOM 729 C LEU A 97 -14.761 2.144 -13.861 1.00 0.00 <br />
ATOM 730 O LEU A 97 -14.368 2.492 -12.747 1.00 0.00 <br />
ATOM 731 CB LEU A 97 -14.474 -0.283 -14.303 1.00 0.00 <br />
ATOM 732 CG LEU A 97 -13.732 -1.432 -14.998 1.00 0.00 <br />
ATOM 733 CD1 LEU A 97 -14.256 -2.769 -14.495 1.00 0.00 <br />
ATOM 734 CD2 LEU A 97 -13.910 -1.313 -16.508 1.00 0.00 <br />
ATOM 735 N ILE A 98 -15.865 2.618 -14.428 1.00 0.00 <br />
ATOM 736 CA ILE A 98 -16.720 3.582 -13.753 1.00 0.00 <br />
ATOM 737 C ILE A 98 -18.046 2.901 -13.478 1.00 0.00 <br />
ATOM 738 O ILE A 98 -18.666 2.370 -14.400 1.00 0.00 <br />
ATOM 739 CB ILE A 98 -17.013 4.822 -14.628 1.00 0.00 <br />
ATOM 740 CG1 ILE A 98 -15.711 5.516 -15.032 1.00 0.00 <br />
ATOM 741 CG2 ILE A 98 -17.929 5.777 -13.861 1.00 0.00 <br />
ATOM 742 CD1 ILE A 98 -14.936 6.099 -13.871 1.00 0.00 <br />
ATOM 743 N PHE A 99 -18.476 2.921 -12.217 1.00 0.00 <br />
ATOM 744 CA PHE A 99 -19.741 2.310 -11.814 1.00 0.00 <br />
ATOM 745 C PHE A 99 -20.619 3.308 -11.065 1.00 0.00 <br />
ATOM 746 O PHE A 99 -20.193 3.871 -10.056 1.00 0.00 <br />
ATOM 747 CB PHE A 99 -19.500 1.114 -10.882 1.00 0.00 <br />
ATOM 748 CG PHE A 99 -19.076 -0.153 -11.583 1.00 0.00 <br />
ATOM 749 CD1 PHE A 99 -20.014 -0.953 -12.233 1.00 0.00 <br />
ATOM 750 CD2 PHE A 99 -17.749 -0.566 -11.554 1.00 0.00 <br />
ATOM 751 CE1 PHE A 99 -19.630 -2.152 -12.841 1.00 0.00 <br />
ATOM 752 CE2 PHE A 99 -17.354 -1.757 -12.157 1.00 0.00 <br />
ATOM 753 CZ PHE A 99 -18.295 -2.554 -12.801 1.00 0.00 <br />
ATOM 754 N ASP A 100 -21.832 3.531 -11.567 1.00 0.00 <br />
ATOM 755 CA ASP A 100 -22.802 4.417 -10.919 1.00 0.00 <br />
ATOM 756 C ASP A 100 -23.593 3.425 -10.072 1.00 0.00 <br />
ATOM 757 O ASP A 100 -24.371 2.636 -10.609 1.00 0.00 <br />
ATOM 758 CB ASP A 100 -23.724 5.061 -11.962 1.00 0.00 <br />
ATOM 759 CG ASP A 100 -24.763 5.989 -11.343 1.00 0.00 <br />
ATOM 760 OD1 ASP A 100 -25.159 5.770 -10.176 1.00 0.00 <br />
ATOM 761 OD2 ASP A 100 -25.198 6.931 -12.040 1.00 0.00 <br />
ATOM 762 N VAL A 101 -23.385 3.462 -8.761 1.00 0.00 <br />
ATOM 763 CA VAL A 101 -24.031 2.520 -7.849 1.00 0.00 <br />
ATOM 764 C VAL A 101 -24.972 3.155 -6.828 1.00 0.00 <br />
ATOM 765 O VAL A 101 -24.646 4.181 -6.223 1.00 0.00 <br />
ATOM 766 CB VAL A 101 -22.950 1.715 -7.068 1.00 0.00 <br />
ATOM 767 CG1 VAL A 101 -23.601 0.831 -6.002 1.00 0.00 <br />
ATOM 768 CG2 VAL A 101 -22.130 0.866 -8.039 1.00 0.00 <br />
ATOM 769 N GLU A 102 -26.132 2.535 -6.635 1.00 0.00 <br />
ATOM 770 CA GLU A 102 -27.102 3.019 -5.652 1.00 0.00 <br />
ATOM 771 C GLU A 102 -27.435 1.886 -4.674 1.00 0.00 <br />
ATOM 772 O GLU A 102 -27.954 0.845 -5.079 1.00 0.00 <br />
ATOM 773 CB GLU A 102 -28.390 3.503 -6.335 1.00 0.00 <br />
ATOM 774 CG GLU A 102 -29.434 3.975 -5.324 1.00 0.00 <br />
ATOM 775 CD GLU A 102 -30.725 4.468 -5.956 1.00 0.00 <br />
ATOM 776 OE1 GLU A 102 -30.943 4.228 -7.167 1.00 0.00 <br />
ATOM 777 OE2 GLU A 102 -31.531 5.086 -5.224 1.00 0.00 <br />
ATOM 778 N LEU A 103 -27.117 2.088 -3.392 1.00 0.00 <br />
ATOM 779 CA LEU A 103 -27.380 1.085 -2.366 1.00 0.00 <br />
ATOM 780 C LEU A 103 -28.842 1.202 -1.953 1.00 0.00 <br />
ATOM 781 O LEU A 103 -29.199 2.007 -1.094 1.00 0.00 <br />
ATOM 782 CB LEU A 103 -26.468 1.305 -1.156 1.00 0.00 <br />
ATOM 783 CG LEU A 103 -26.609 0.303 -0.005 1.00 0.00 <br />
ATOM 784 CD1 LEU A 103 -26.382 -1.118 -0.505 1.00 0.00 <br />
ATOM 785 CD2 LEU A 103 -25.609 0.653 1.081 1.00 0.00 <br />
ATOM 786 N LEU A 104 -29.675 0.377 -2.570 1.00 0.00 <br />
ATOM 787 CA LEU A 104 -31.111 0.393 -2.332 1.00 0.00 <br />
ATOM 788 C LEU A 104 -31.576 -0.236 -1.027 1.00 0.00 <br />
ATOM 789 O LEU A 104 -32.426 0.320 -0.330 1.00 0.00 <br />
ATOM 790 CB LEU A 104 -31.816 -0.302 -3.490 1.00 0.00 <br />
ATOM 791 CG LEU A 104 -31.473 0.249 -4.875 1.00 0.00 <br />
ATOM 792 CD1 LEU A 104 -31.942 -0.729 -5.949 1.00 0.00 <br />
ATOM 793 CD2 LEU A 104 -32.120 1.615 -5.046 1.00 0.00 <br />
ATOM 794 N ASN A 105 -31.021 -1.393 -0.691 1.00 0.00 <br />
ATOM 795 CA ASN A 105 -31.449 -2.075 0.517 1.00 0.00 <br />
ATOM 796 C ASN A 105 -30.377 -3.035 1.005 1.00 0.00 <br />
ATOM 797 O ASN A 105 -29.434 -3.353 0.276 1.00 0.00 <br />
ATOM 798 CB ASN A 105 -32.746 -2.835 0.206 1.00 0.00 <br />
ATOM 799 CG ASN A 105 -33.449 -3.342 1.448 1.00 0.00 <br />
ATOM 800 OD1 ASN A 105 -33.342 -2.754 2.523 1.00 0.00 <br />
ATOM 801 ND2 ASN A 105 -34.195 -4.431 1.298 1.00 0.00 <br />
ATOM 802 N LEU A 106 -30.524 -3.481 2.248 1.00 0.00 <br />
ATOM 803 CA LEU A 106 -29.600 -4.429 2.856 1.00 0.00 <br />
ATOM 804 C LEU A 106 -30.427 -5.586 3.404 1.00 0.00 <br />
ATOM 805 O LEU A 106 -31.322 -5.377 4.224 1.00 0.00 <br />
ATOM 806 CB LEU A 106 -28.812 -3.754 3.981 1.00 0.00 <br />
ATOM 807 CG LEU A 106 -27.682 -2.843 3.494 1.00 0.00 <br />
ATOM 808 CD1 LEU A 106 -27.164 -1.983 4.632 1.00 0.00 <br />
ATOM 809 CD2 LEU A 106 -26.563 -3.714 2.914 1.00 0.00 <br />
ATOM 810 N GLU A 107 -30.132 -6.800 2.946 1.00 0.00 <br />
ATOM 811 CA GLU A 107 -30.875 -7.980 3.382 1.00 0.00 <br />
ATOM 812 C GLU A 107 -29.979 -9.012 4.061 1.00 0.00 <br />
ATOM 813 O GLU A 107 -28.799 -8.767 4.306 1.00 0.00 <br />
ATOM 814 CB GLU A 107 -31.571 -8.626 2.183 1.00 0.00 <br />
ATOM 815 CG GLU A 107 -32.261 -7.635 1.263 1.00 0.00 <br />
ATOM 816 CD GLU A 107 -32.909 -8.302 0.067 1.00 0.00 <br />
ATOM 817 OE1 GLU A 107 -32.510 -9.436 -0.265 1.00 0.00 <br />
ATOM 818 OE2 GLU A 107 -33.806 -7.687 -0.549 1.00 0.00 <br />
TER<br />
ATOM 819 C1 RAP A 108 -18.510 -8.134 -11.063 1.00 0.00 <br />
ATOM 820 O1 RAP A 108 -18.969 -9.229 -11.856 1.00 0.00 <br />
ATOM 821 O2 RAP A 108 -17.819 -8.381 -10.069 1.00 0.00 <br />
ATOM 822 C2 RAP A 108 -18.857 -6.680 -11.413 1.00 0.00 <br />
ATOM 823 C3 RAP A 108 -19.378 -5.903 -10.192 1.00 0.00 <br />
ATOM 824 C4 RAP A 108 -20.810 -6.269 -9.768 1.00 0.00 <br />
ATOM 825 C5 RAP A 108 -21.748 -6.104 -10.968 1.00 0.00 <br />
ATOM 826 C6 RAP A 108 -21.289 -6.956 -12.126 1.00 0.00 <br />
ATOM 827 N7 RAP A 108 -19.893 -6.531 -12.486 1.00 0.00 <br />
ATOM 828 C8 RAP A 108 -19.513 -6.171 -13.744 1.00 0.00 <br />
ATOM 829 O3 RAP A 108 -18.296 -5.996 -13.976 1.00 0.00 <br />
ATOM 830 C9 RAP A 108 -20.424 -5.985 -14.822 1.00 0.00 <br />
ATOM 831 O4 RAP A 108 -21.015 -4.900 -14.935 1.00 0.00 <br />
ATOM 832 C10 RAP A 108 -20.701 -7.102 -15.860 1.00 0.00 <br />
ATOM 833 O5 RAP A 108 -21.536 -8.043 -15.186 1.00 0.00 <br />
ATOM 834 O6 RAP A 108 -21.405 -6.534 -16.979 1.00 0.00 <br />
ATOM 835 C11 RAP A 108 -19.388 -7.854 -16.375 1.00 0.00 <br />
ATOM 836 C12 RAP A 108 -19.775 -9.075 -17.246 1.00 0.00 <br />
ATOM 837 C13 RAP A 108 -20.761 -9.975 -16.480 1.00 0.00 <br />
ATOM 838 C14 RAP A 108 -21.967 -9.211 -15.854 1.00 0.00 <br />
ATOM 839 C15 RAP A 108 -22.672 -10.085 -14.824 1.00 0.00 <br />
ATOM 840 C16 RAP A 108 -23.453 -11.289 -15.379 1.00 0.00 <br />
ATOM 841 O7 RAP A 108 -24.420 -10.794 -16.279 1.00 0.00 <br />
ATOM 842 C17 RAP A 108 -24.142 -12.089 -14.269 1.00 0.00 <br />
ATOM 843 C18 RAP A 108 -23.665 -13.315 -13.987 1.00 0.00 <br />
ATOM 844 C19 RAP A 108 -24.201 -14.242 -12.966 1.00 0.00 <br />
ATOM 845 C20 RAP A 108 -23.630 -15.435 -12.786 1.00 0.00 <br />
ATOM 846 C21 RAP A 108 -24.162 -16.384 -11.781 1.00 0.00 <br />
ATOM 847 C22 RAP A 108 -23.444 -17.370 -11.268 1.00 0.00 <br />
ATOM 848 C23 RAP A 108 -23.906 -18.220 -10.081 1.00 0.00 <br />
ATOM 849 C24 RAP A 108 -22.851 -18.127 -8.963 1.00 0.00 <br />
ATOM 850 C25 RAP A 108 -22.360 -16.747 -8.519 1.00 0.00 <br />
ATOM 851 C26 RAP A 108 -21.023 -16.845 -7.774 1.00 0.00 <br />
ATOM 852 O8 RAP A 108 -20.965 -16.994 -6.547 1.00 0.00 <br />
ATOM 853 C27 RAP A 108 -19.745 -16.757 -8.633 1.00 0.00 <br />
ATOM 854 O9 RAP A 108 -18.698 -17.397 -7.951 1.00 0.00 <br />
ATOM 855 C28 RAP A 108 -19.234 -15.293 -8.931 1.00 0.00 <br />
ATOM 856 O10 RAP A 108 -19.259 -14.553 -7.701 1.00 0.00 <br />
ATOM 857 C29 RAP A 108 -20.070 -14.540 -10.006 1.00 0.00 <br />
ATOM 858 C30 RAP A 108 -20.851 -13.477 -9.720 1.00 0.00 <br />
ATOM 859 C31 RAP A 108 -21.739 -12.610 -10.632 1.00 0.00 <br />
ATOM 860 C32 RAP A 108 -21.031 -11.274 -10.909 1.00 0.00 <br />
ATOM 861 O11 RAP A 108 -21.295 -10.239 -10.286 1.00 0.00 <br />
ATOM 862 C33 RAP A 108 -19.966 -11.303 -12.008 1.00 0.00 <br />
ATOM 863 C34 RAP A 108 -18.698 -10.575 -11.585 1.00 0.00 <br />
ATOM 864 C35 RAP A 108 -17.359 -10.916 -12.304 1.00 0.00 <br />
ATOM 865 C36 RAP A 108 -16.786 -12.266 -11.815 1.00 0.00 <br />
ATOM 866 C37 RAP A 108 -16.322 -12.376 -10.346 1.00 0.00 <br />
ATOM 867 C38 RAP A 108 -15.790 -13.811 -10.060 1.00 0.00 <br />
ATOM 868 C39 RAP A 108 -15.278 -14.019 -8.595 1.00 0.00 <br />
ATOM 869 O12 RAP A 108 -14.646 -15.301 -8.504 1.00 0.00 <br />
ATOM 870 C40 RAP A 108 -14.253 -12.869 -8.176 1.00 0.00 <br />
ATOM 871 O13 RAP A 108 -14.019 -12.970 -6.766 1.00 0.00 <br />
ATOM 872 C41 RAP A 108 -14.775 -11.432 -8.497 1.00 0.00 <br />
ATOM 873 C42 RAP A 108 -15.251 -11.324 -9.952 1.00 0.00 <br />
ATOM 874 C43 RAP A 108 -18.390 -6.936 -17.162 1.00 0.00 <br />
ATOM 875 C44 RAP A 108 -25.350 -11.389 -13.580 1.00 0.00 <br />
ATOM 876 C45 RAP A 108 -24.081 -19.670 -10.522 1.00 0.00 <br />
ATOM 877 C46 RAP A 108 -23.414 -16.041 -7.644 1.00 0.00 <br />
ATOM 878 C47 RAP A 108 -19.924 -15.115 -11.414 1.00 0.00 <br />
ATOM 879 C48 RAP A 108 -23.101 -12.375 -9.939 1.00 0.00 <br />
ATOM 880 C49 RAP A 108 -17.519 -10.949 -13.817 1.00 0.00 <br />
ATOM 881 C50 RAP A 108 -24.780 -11.612 -17.353 1.00 0.00 <br />
ATOM 882 C51 RAP A 108 -18.394 -18.690 -8.368 1.00 0.00 <br />
ATOM 883 C52 RAP A 108 -13.537 -15.605 -9.312 1.00 0.00 <br />
ATOM 884 O MOL 1 -14.467 -0.075 1.713 1.00 0.00 <br />
ATOM 885 O MOL 1 -3.747 -10.364 -12.950 1.00 0.00 <br />
ATOM 886 O MOL 1 -3.863 1.423 -20.222 1.00 0.00 <br />
ATOM 887 O MOL 1 -33.153 2.955 -17.490 1.00 0.00 <br />
ATOM 888 O MOL 1 -11.437 -10.318 -9.024 1.00 0.00 <br />
ATOM 889 O MOL 1 -8.994 -5.070 -17.002 1.00 0.00 <br />
ATOM 890 O MOL 1 -16.599 7.684 0.589 1.00 0.00 <br />
ATOM 891 O MOL 1 -10.617 -3.779 -15.257 1.00 0.00 <br />
ATOM 892 O MOL 1 -7.744 -0.765 -21.451 1.00 0.00 <br />
ATOM 893 O MOL 1 -30.531 10.772 -1.245 1.00 0.00 <br />
ATOM 894 O MOL 1 -9.991 5.189 -8.561 1.00 0.00 <br />
ATOM 895 O MOL 1 -15.383 8.367 -8.819 1.00 0.00 <br />
ATOM 896 O MOL 1 -22.582 7.719 3.484 1.00 0.00 <br />
ATOM 897 O MOL 1 -31.535 6.282 3.044 1.00 0.00 <br />
ATOM 898 O MOL 1 -6.221 -11.354 -21.344 1.00 0.00 <br />
ATOM 899 O MOL 1 -30.986 8.365 -2.508 1.00 0.00 <br />
ATOM 900 O MOL 1 -26.122 5.808 -14.288 1.00 0.00 <br />
ATOM 901 O MOL 1 -28.681 6.587 -14.636 1.00 0.00 <br />
ATOM 902 O MOL 1 -30.242 9.407 -6.889 1.00 0.00 <br />
ATOM 903 O MOL 1 -4.086 -4.225 -12.418 1.00 0.00 <br />
ATOM 904 O MOL 1 -13.558 9.340 -12.463 1.00 0.00 <br />
ATOM 905 O MOL 1 -24.024 9.804 2.183 1.00 0.00 <br />
ATOM 906 O MOL 1 -28.911 -10.292 -8.292 1.00 0.00 <br />
ATOM 907 O MOL 1 -10.002 -11.107 -20.617 1.00 0.00 <br />
ATOM 908 O MOL 1 -3.379 -1.268 -11.644 1.00 0.00 <br />
ATOM 909 O MOL 1 -3.814 -6.433 -11.116 1.00 0.00 <br />
ATOM 910 O MOL 1 -6.811 1.796 -20.467 1.00 0.00 <br />
ATOM 911 O MOL 1 -5.042 0.450 -5.739 1.00 0.00 <br />
ATOM 912 O MOL 1 -13.226 8.110 -2.465 1.00 0.00 <br />
ATOM 913 O MOL 1 -11.705 -0.385 1.598 1.00 0.00 <br />
ATOM 914 O MOL 1 -26.811 -13.511 -10.984 1.00 0.00 <br />
ATOM 915 O MOL 1 -12.132 3.844 -1.192 1.00 0.00 <br />
ATOM 916 O MOL 1 -12.915 6.445 -0.256 1.00 0.00 <br />
ATOM 917 O MOL 1 -14.006 10.177 -15.559 1.00 0.00 <br />
ATOM 918 O MOL 1 -6.462 2.069 -16.582 1.00 0.00 <br />
ATOM 919 O MOL 1 -21.593 -5.761 -22.112 1.00 0.00 <br />
ATOM 920 O MOL 1 -22.112 4.659 11.361 1.00 0.00 <br />
ATOM 921 O MOL 1 -24.505 -7.743 -19.597 1.00 0.00 <br />
ATOM 922 O MOL 1 -2.660 -0.168 -14.034 1.00 0.00 <br />
ATOM 923 O MOL 1 -2.685 -8.544 -20.622 1.00 0.00 <br />
ATOM 924 O MOL 1 -30.204 4.761 -16.268 1.00 0.00 <br />
ATOM 925 O MOL 1 -1.421 1.865 -16.896 1.00 0.00 <br />
ATOM 926 O MOL 1 -22.558 11.507 0.921 1.00 0.00 <br />
ATOM 927 O MOL 1 -32.805 11.307 0.058 1.00 0.00 <br />
ATOM 928 O MOL 1 -3.446 -8.060 -13.318 1.00 0.00 <br />
ATOM 929 O MOL 1 -29.831 4.936 -9.378 1.00 0.00 <br />
ATOM 930 O MOL 1 -7.164 5.063 -13.547 1.00 0.00 <br />
ATOM 931 O MOL 1 -4.420 2.292 -14.820 1.00 0.00 <br />
ATOM 932 O MOL 1 -5.770 -9.954 -14.183 1.00 0.00 <br />
ATOM 933 O MOL 1 -27.557 -11.487 -9.884 1.00 0.00 <br />
ATOM 934 O MOL 1 -31.664 4.503 -2.445 1.00 0.00 <br />
ATOM 935 O MOL 1 -25.729 -8.264 -16.380 1.00 0.00 <br />
ATOM 936 O MOL 1 -21.969 10.396 5.765 1.00 0.00 <br />
ATOM 937 O MOL 1 -7.004 -0.510 -2.928 1.00 0.00 <br />
ATOM 938 O MOL 1 -30.875 7.805 -13.213 1.00 0.00 <br />
ATOM 939 O MOL 1 -18.401 12.641 -2.383 1.00 0.00 <br />
ATOM 940 O MOL 1 -18.898 -7.605 -25.486 1.00 0.00 <br />
ATOM 941 O MOL 1 -25.575 -5.788 -20.825 1.00 0.00 <br />
ATOM 942 O MOL 1 -7.654 5.064 -6.946 1.00 0.00 <br />
ATOM 943 O MOL 1 -10.256 -9.151 -22.336 1.00 0.00 <br />
ATOM 944 O MOL 1 -19.822 -4.848 -24.124 1.00 0.00 <br />
ATOM 945 O MOL 1 -23.526 -17.086 -4.354 1.00 0.00 <br />
ATOM 946 O MOL 1 -18.719 -10.494 -2.408 1.00 0.00 <br />
ATOM 947 O MOL 1 -17.490 -3.388 -23.343 1.00 0.00 <br />
ATOM 948 O MOL 1 -30.962 10.093 -11.750 1.00 0.00 <br />
ATOM 949 O MOL 1 -18.908 -1.315 -28.688 1.00 0.00 <br />
ATOM 950 O MOL 1 -3.124 -4.146 -15.431 1.00 0.00 <br />
ATOM 951 O MOL 1 -9.221 2.699 -18.647 1.00 0.00 <br />
ATOM 952 O MOL 1 -11.056 -7.239 -8.343 1.00 0.00 <br />
ATOM 953 O MOL 1 -13.633 -12.173 -15.090 1.00 0.00 <br />
ATOM 954 O MOL 1 -15.513 -10.202 -0.432 1.00 0.00 <br />
ATOM 955 O MOL 1 -28.234 2.974 -16.765 1.00 0.00 <br />
ATOM 956 O MOL 1 -15.150 1.628 -25.119 1.00 0.00 <br />
ATOM 957 O MOL 1 -27.057 11.649 5.648 1.00 0.00 <br />
ATOM 958 O MOL 1 -35.417 1.166 -8.176 1.00 0.00 <br />
ATOM 959 O MOL 1 -32.217 9.638 -9.089 1.00 0.00 <br />
ATOM 960 O MOL 1 -19.494 6.929 1.151 1.00 0.00 <br />
ATOM 961 O MOL 1 -9.252 2.616 -2.781 1.00 0.00 <br />
ATOM 962 O MOL 1 -24.348 -8.092 -23.126 1.00 0.00 <br />
ATOM 963 O MOL 1 -21.693 -7.243 -19.749 1.00 0.00 <br />
ATOM 964 O MOL 1 -11.065 8.058 -14.677 1.00 0.00 <br />
ATOM 965 O MOL 1 -21.355 0.992 -27.640 1.00 0.00 <br />
ATOM 966 O MOL 1 -8.191 6.228 -11.230 1.00 0.00 <br />
ATOM 967 O MOL 1 -1.738 -5.828 -9.719 1.00 0.00 <br />
ATOM 968 O MOL 1 -5.954 3.838 -4.110 1.00 0.00 <br />
ATOM 969 O MOL 1 -0.305 -0.954 -13.761 1.00 0.00 <br />
ATOM 970 O MOL 1 -35.121 9.765 -8.231 1.00 0.00 <br />
ATOM 971 O MOL 1 -9.195 7.921 -12.896 1.00 0.00 <br />
ATOM 972 O MOL 1 -11.412 -8.346 -24.443 1.00 0.00 <br />
ATOM 973 O MOL 1 -18.575 -4.730 5.949 1.00 0.00 <br />
ATOM 974 O MOL 1 -24.572 -2.651 -22.639 1.00 0.00 <br />
ATOM 975 O MOL 1 -17.538 -17.548 -1.182 1.00 0.00 <br />
ATOM 976 O MOL 1 -28.405 1.980 11.352 1.00 0.00 <br />
ATOM 977 O MOL 1 -27.591 2.765 -19.420 1.00 0.00 <br />
ATOM 978 O MOL 1 -17.468 7.579 -21.396 1.00 0.00 <br />
ATOM 979 O MOL 1 -31.391 9.463 3.968 1.00 0.00 <br />
ATOM 980 O MOL 1 -24.855 11.287 4.464 1.00 0.00 <br />
ATOM 981 O MOL 1 -32.329 -2.161 4.687 1.00 0.00 <br />
ATOM 982 O MOL 1 -31.502 -1.553 7.124 1.00 0.00 <br />
ATOM 983 O MOL 1 -5.167 -3.927 -5.363 1.00 0.00 <br />
ATOM 984 O MOL 1 -12.442 -12.583 -11.643 1.00 0.00 <br />
TER</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
<br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin </font size></font color> <sup>6,7</sup><br />
<br><br />
<br />
Rapamycin is a very complicated molecule. It had a 31 memembered ring, and also possesses many chiral centres, and different functional groups. Due to its complexity, it has proved a challenge to synthesise for many synthetic chemists. <br />
Methods have therefore been suggested, to prepare fragments of the molecule, and then combine them to get the total molecule of rapamycin.<br />
<br />
The first fragment prepared is the fragment from C<sub>10</sub> to C<sub>21</sub>. <br />
The starting material used is (R)-methyl 3-hydroxy-2-methylpropionate. This is converted to an alcohol in a four step reaction, as shown below:<br />
<br />
[[Image:synthesisstep.gif]]<br />
<br />
<br />
Then from this molecule, further complicated synthesis steps yield the following fragment:<br />
<br />
[[Image:Fragment1.gif]]<br />
<br />
<br />
The second fragment prepared is the fragment from C<sub>22</sub> - C<sub>42</sub>. This is prepared through complicated synthetic methods. The second fragment obtained is shown below:<br />
<br />
[[Image:Fragment2.gif]]<br />
<br />
The second fragment was then combined with the first fragment under certain required conditions, yielding the synthetic rapamycin, which was judged as identical to the natural occuring rapamycin molecule through comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.<br />
<br />
The various complicated synthesis steps, and conditions are all in the cited journals, from which this all synthetic information was gained.<br />
<br />
Rapamycin can also be synthesised by using trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH<sub>3</sub>CN)<sub>2</sub> C<sub>12</sub>, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
However, the starting material is hard to synthesise, so is usually only the fragment method of synthesis is used for synthetic rapamycin production<br />
<br />
<br />
<br />
<br />
<font size=5><font color=red>History of Rapamycin</font size></font color><sup>10</sup><br><br />
<br><br />
[http://en.wikipedia.org/wiki/Rapamycin''Rapamycin''] is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs([http://en.wikipedia.org/wiki/RNA''RNA'']) selectively, which is the most notably mRNAs encoding [http://en.wikipedia.org/wiki/Ribosomal_protein''ribosomal proteins''] and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a [http://en.wikipedia.org/wiki/Polyketide''polyketide''] pathway. The polyketide chain is formed by condensation of seven [http://en.wikipedia.org/wiki/Acetate''acetate''] components and same number of [http://en.wikipedia.org/wiki/Propionate''propionate''] units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<br />
<jmol><br />
<jmolApplet><br />
<size>400</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY QEKNID<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 20.690 22.560 11.220 90.00 90.00 90.00 P 21 21 21 4<br />
ATOM 1 O1 UNK 0 1 1.401 8.009 6.161 1.00 0.00<br />
ATOM 2 O2 UNK 0 1 1.535 9.421 3.430 1.00 0.00<br />
ATOM 3 O3 UNK 0 1 4.165 9.543 3.068 1.00 0.00<br />
ATOM 4 O4 UNK 0 1 6.290 5.800 0.411 1.00 0.00<br />
ATOM 5 O5 UNK 0 1 3.617 0.984 6.788 1.00 0.00<br />
ATOM 6 O6 UNK 0 1 1.988 4.661 5.821 1.00 0.00<br />
ATOM 7 O7 UNK 0 1 3.414 10.078 11.631 1.00 0.00<br />
ATOM 8 O8 UNK 0 1 4.926 9.642 9.448 1.00 0.00<br />
ATOM 9 O9 UNK 0 1 0.134 3.788 6.711 1.00 0.00<br />
ATOM 10 O10 UNK 0 1 8.545 -2.658 8.213 1.00 0.00<br />
ATOM 11 O11 UNK 0 1 3.877 7.255 3.373 1.00 0.00<br />
ATOM 12 O12 UNK 0 1 8.348 1.263 9.851 1.00 0.00<br />
ATOM 13 O13 UNK 0 1 9.710 -0.957 9.885 1.00 0.00<br />
ATOM 14 N1 UNK 0 1 0.821 6.574 4.485 1.00 0.00<br />
ATOM 15 C1 UNK 0 1 2.847 3.804 6.597 1.00 0.00<br />
ATOM 16 C2 UNK 0 1 2.137 8.591 4.006 1.00 0.00<br />
ATOM 17 C3 UNK 0 1 5.253 5.566 2.525 1.00 0.00<br />
ATOM 18 C4 UNK 0 1 6.439 0.772 7.035 1.00 0.00<br />
ATOM 19 C5 UNK 0 1 5.760 1.455 5.879 1.00 0.00<br />
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ATOM 21 C7 UNK 0 1 4.372 8.706 5.296 1.00 0.00<br />
ATOM 22 C8 UNK 0 1 0.685 4.598 6.025 1.00 0.00<br />
ATOM 23 C9 UNK 0 1 1.444 7.657 4.993 1.00 0.00<br />
ATOM 24 C10 UNK 0 1 5.266 6.987 3.074 1.00 0.00<br />
ATOM 25 C11 UNK 0 1 9.484 1.514 2.917 1.00 0.00<br />
ATOM 26 C12 UNK 0 1 6.546 5.254 1.728 1.00 0.00<br />
ATOM 27 C13 UNK 0 1 0.002 5.764 5.363 1.00 0.00<br />
ATOM 28 C14 UNK 0 1 6.873 3.770 1.616 1.00 0.00<br />
ATOM 29 C15 UNK 0 1 5.845 8.444 5.027 1.00 0.00<br />
ATOM 30 C16 UNK 0 1 4.643 3.941 8.471 1.00 0.00<br />
ATOM 31 C17 UNK 0 1 4.175 10.062 5.891 1.00 0.00<br />
ATOM 32 C18 UNK 0 1 6.062 7.106 4.353 1.00 0.00<br />
ATOM 33 C19 UNK 0 1 1.130 5.996 3.130 1.00 0.00<br />
ATOM 34 C20 UNK 0 1 0.132 5.568 2.424 1.00 0.00<br />
ATOM 35 C21 UNK 0 1 -0.902 4.584 3.310 1.00 0.00<br />
ATOM 36 C22 UNK 0 1 -1.283 5.277 4.634 1.00 0.00<br />
ATOM 37 C23 UNK 0 1 7.333 5.703 -0.449 1.00 0.00<br />
ATOM 38 C24 UNK 0 1 5.787 2.858 0.987 1.00 0.00<br />
ATOM 39 C25 UNK 0 1 4.223 8.521 10.019 1.00 0.00<br />
ATOM 40 C26 UNK 0 1 3.070 9.096 10.659 1.00 0.00<br />
ATOM 41 C27 UNK 0 1 2.162 8.038 11.321 1.00 0.00<br />
ATOM 42 C28 UNK 0 1 1.777 7.000 10.322 1.00 0.00<br />
ATOM 43 C29 UNK 0 1 3.035 6.371 9.593 1.00 0.00<br />
ATOM 44 C30 UNK 0 1 3.813 7.463 8.954 1.00 0.00<br />
ATOM 45 C31 UNK 0 1 4.299 1.800 6.149 1.00 0.00<br />
ATOM 46 C32 UNK 0 1 3.745 3.070 5.621 1.00 0.00<br />
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ATOM 48 C34 UNK 0 1 3.534 4.692 7.641 1.00 0.00<br />
ATOM 49 C35 UNK 0 1 8.028 3.321 2.132 1.00 0.00<br />
ATOM 50 C36 UNK 0 1 8.423 1.922 2.255 1.00 0.00<br />
ATOM 51 C37 UNK 0 1 10.751 -0.223 3.994 1.00 0.00<br />
ATOM 52 C38 UNK 0 1 10.968 -1.676 4.387 1.00 0.00<br />
ATOM 53 C39 UNK 0 1 12.420 -1.994 4.107 1.00 0.00<br />
ATOM 54 C40 UNK 0 1 10.657 -1.852 5.891 1.00 0.00<br />
ATOM 55 C41 UNK 0 1 9.215 -1.475 6.205 1.00 0.00<br />
ATOM 56 C42 UNK 0 1 9.846 0.140 3.119 1.00 0.00<br />
ATOM 57 C43 UNK 0 1 8.266 -2.391 5.430 1.00 0.00<br />
ATOM 58 C44 UNK 0 1 9.019 -1.694 7.697 1.00 0.00<br />
ATOM 59 C45 UNK 0 1 8.460 2.175 7.057 1.00 0.00<br />
ATOM 60 C46 UNK 0 1 6.296 9.389 9.133 1.00 0.00<br />
ATOM 61 C47 UNK 0 1 9.362 -0.492 8.583 1.00 0.00<br />
ATOM 62 C48 UNK 0 1 10.976 -0.887 10.210 1.00 0.00<br />
ATOM 63 C49 UNK 0 1 8.108 0.334 8.785 1.00 0.00<br />
ATOM 64 C50 UNK 0 1 7.606 1.060 7.562 1.00 0.00<br />
ATOM 65 C51 UNK 0 1 5.843 0.575 4.600 1.00 0.00<br />
ATOM 66 H1 UNK 0 1 3.540 9.985 2.615 1.00 0.00<br />
ATOM 67 H2 UNK 0 1 8.210 2.112 9.513 1.00 0.00<br />
ATOM 68 H3 UNK 0 1 5.710 0.147 7.313 1.00 0.00<br />
ATOM 69 H4 UNK 0 1 6.224 2.351 5.476 1.00 0.00<br />
ATOM 70 H5 UNK 0 1 4.030 7.758 6.075 1.00 0.00<br />
ATOM 71 H6 UNK 0 1 10.151 2.085 3.193 1.00 0.00<br />
ATOM 72 H7 UNK 0 1 6.188 9.139 4.429 1.00 0.00<br />
ATOM 73 H8 UNK 0 1 4.260 3.370 9.108 1.00 0.00<br />
ATOM 74 H9 UNK 0 1 3.269 10.154 6.217 1.00 0.00<br />
ATOM 75 H10 UNK 0 1 6.999 6.982 4.170 1.00 0.00<br />
ATOM 76 H11 UNK 0 1 1.572 6.664 2.602 1.00 0.00<br />
ATOM 77 H12 UNK 0 1 -1.748 4.645 5.196 1.00 0.00<br />
ATOM 78 H13 UNK 0 1 5.371 3.343 0.286 1.00 0.00<br />
ATOM 79 H14 UNK 0 1 1.608 6.177 10.770 1.00 0.00<br />
ATOM 80 H15 UNK 0 1 3.428 5.947 10.188 1.00 0.00<br />
ATOM 81 H16 UNK 0 1 4.802 7.221 8.586 1.00 0.00<br />
ATOM 82 H17 UNK 0 1 3.548 7.930 8.237 1.00 0.00<br />
ATOM 83 H18 UNK 0 1 3.271 2.897 4.825 1.00 0.00<br />
ATOM 84 H19 UNK 0 1 1.879 5.827 7.973 1.00 0.00<br />
ATOM 85 H20 UNK 0 1 3.960 5.331 7.139 1.00 0.00<br />
ATOM 86 H21 UNK 0 1 8.382 3.858 2.781 1.00 0.00<br />
ATOM 87 H22 UNK 0 1 10.258 -2.409 3.883 1.00 0.00<br />
ATOM 88 H23 UNK 0 1 12.704 -2.786 4.518 1.00 0.00<br />
ATOM 89 H24 UNK 0 1 10.659 -2.732 5.892 1.00 0.00<br />
ATOM 90 H25 UNK 0 1 11.239 -1.078 6.572 1.00 0.00<br />
ATOM 91 H26 UNK 0 1 9.195 -0.305 5.991 1.00 0.00<br />
ATOM 92 H27 UNK 0 1 9.112 -0.650 2.517 1.00 0.00<br />
ATOM 93 H28 UNK 0 1 8.466 -3.298 5.647 1.00 0.00<br />
ATOM 94 H29 UNK 0 1 8.322 2.955 7.548 1.00 0.00<br />
ATOM 95 H30 UNK 0 1 6.714 10.132 8.706 1.00 0.00<br />
ATOM 96 H31 UNK 0 1 6.391 8.622 8.547 1.00 0.00<br />
ATOM 97 H32 UNK 0 1 7.293 -0.210 9.074 1.00 0.00<br />
ATOM 98 H33 UNK 0 1 5.866 -0.356 4.865 1.00 0.00<br />
ATOM 99 H34 UNK 0 1 5.183 4.941 3.258 1.00 0.00<br />
ATOM 100 H35 UNK 0 1 7.519 4.789 -0.649 1.00 0.00<br />
ATOM 101 H36 UNK 0 1 7.190 6.184 -1.241 1.00 0.00<br />
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ATOM 103 H38 UNK 0 1 8.011 1.087 1.694 1.00 0.00<br />
ATOM 104 H39 UNK 0 1 12.617 -2.003 3.181 1.00 0.00<br />
ATOM 105 H40 UNK 0 1 7.366 -2.209 5.718 1.00 0.00<br />
ATOM 106 H41 UNK 0 1 11.307 0.449 4.388 1.00 0.00<br />
ATOM 107 H42 UNK 0 1 -0.679 6.317 2.243 1.00 0.00<br />
ATOM 108 H43 UNK 0 1 0.095 5.141 1.592 1.00 0.00<br />
ATOM 109 H44 UNK 0 1 5.144 2.624 1.641 1.00 0.00<br />
ATOM 110 H45 UNK 0 1 6.209 2.089 0.650 1.00 0.00<br />
ATOM 111 H46 UNK 0 1 -1.872 6.010 4.470 1.00 0.00<br />
ATOM 112 H47 UNK 0 1 1.713 5.252 3.228 1.00 0.00<br />
ATOM 113 H48 UNK 0 1 -0.294 6.351 6.059 1.00 0.00<br />
ATOM 114 H49 UNK 0 1 5.175 3.393 7.855 1.00 0.00<br />
ATOM 115 H50 UNK 0 1 5.228 4.559 8.877 1.00 0.00<br />
ATOM 116 H51 UNK 0 1 2.023 4.681 9.009 1.00 0.00<br />
ATOM 117 H52 UNK 0 1 1.378 8.478 11.672 1.00 0.00<br />
ATOM 118 H53 UNK 0 1 2.549 9.527 9.980 1.00 0.00<br />
ATOM 119 H54 UNK 0 1 4.759 8.106 10.676 1.00 0.00<br />
ATOM 120 H55 UNK 0 1 6.811 9.184 9.931 1.00 0.00<br />
ATOM 121 H56 UNK 0 1 3.064 10.019 12.513 1.00 0.00<br />
ATOM 122 H57 UNK 0 1 5.046 0.704 4.082 1.00 0.00<br />
ATOM 123 H58 UNK 0 1 6.596 0.778 4.098 1.00 0.00<br />
ATOM 124 H59 UNK 0 1 9.391 1.922 7.099 1.00 0.00<br />
ATOM 125 H60 UNK 0 1 8.249 2.330 6.128 1.00 0.00<br />
ATOM 126 H61 UNK 0 1 11.301 -0.034 10.172 1.00 0.00<br />
ATOM 127 H62 UNK 0 1 8.344 -2.245 4.515 1.00 0.00<br />
ATOM 128 H63 UNK 0 1 12.991 -1.261 4.491 1.00 0.00<br />
ATOM 129 H64 UNK 0 1 7.291 5.701 2.119 1.00 0.00<br />
ATOM 130 H65 UNK 0 1 4.496 5.446 1.961 1.00 0.00<br />
ATOM 131 H66 UNK 0 1 5.609 7.596 2.424 1.00 0.00<br />
ATOM 132 H67 UNK 0 1 6.352 8.496 5.832 1.00 0.00<br />
ATOM 133 H68 UNK 0 1 4.769 10.215 6.611 1.00 0.00<br />
ATOM 134 H69 UNK 0 1 4.308 10.741 5.225 1.00 0.00<br />
ATOM 135 H70 UNK 0 1 2.319 3.147 7.060 1.00 0.00<br />
ATOM 136 H71 UNK 0 1 5.793 6.418 4.966 1.00 0.00<br />
ATOM 137 H72 UNK 0 1 -1.823 4.302 2.821 1.00 0.00<br />
ATOM 138 H73 UNK 0 1 -0.339 3.831 3.457 1.00 0.00<br />
ATOM 139 H74 UNK 0 1 8.137 6.064 -0.019 1.00 0.00<br />
ATOM 140 H75 UNK 0 1 2.630 7.650 12.060 1.00 0.00<br />
ATOM 141 H76 UNK 0 1 4.498 3.646 5.411 1.00 0.00<br />
ATOM 142 H77 UNK 0 1 11.137 -1.200 11.098 1.00 0.00<br />
ATOM 143 H78 UNK 0 1 11.531 -1.392 9.609 1.00 0.00<br />
ATOM 144 H79 UNK 0 1 10.095 0.059 8.192 1.00 0.00<br />
ATOM 145 H80 UNK 0 1 6.443 3.641 2.498 1.00 0.00<br />
CONECT 1 23<br />
CONECT 2 16<br />
CONECT 3 20 66<br />
CONECT 4 26 37<br />
CONECT 5 45<br />
CONECT 6 15 22<br />
CONECT 7 40 121<br />
CONECT 8 39 60<br />
CONECT 9 22<br />
CONECT 10 58<br />
CONECT 11 20 24<br />
CONECT 12 63 67<br />
CONECT 13 61 62<br />
CONECT 14 23 27 33<br />
CONECT 15 6 46 48 135<br />
CONECT 16 2 20 23<br />
CONECT 17 24 26 99 130<br />
CONECT 18 19 64 68<br />
CONECT 19 18 45 65 69<br />
CONECT 20 3 11 16 21<br />
CONECT 21 20 29 31 70<br />
CONECT 22 6 9 27<br />
CONECT 23 1 14 16<br />
CONECT 24 11 17 32 131<br />
CONECT 25 50 56 71<br />
CONECT 26 4 17 28 129<br />
CONECT 27 14 22 36 113<br />
CONECT 28 26 38 49<br />
CONECT 29 21 32 72 132<br />
CONECT 30 48 73 114 115<br />
CONECT 31 21 74 133 134<br />
CONECT 32 24 29 75 136<br />
CONECT 33 14 34 76 112<br />
CONECT 34 33 35 107 108<br />
CONECT 35 34 36 137 138<br />
CONECT 36 27 35 77 111<br />
CONECT 37 4 100 101 139<br />
CONECT 38 28 78 109 110<br />
CONECT 39 8 40 44 119<br />
CONECT 40 7 39 41 118<br />
CONECT 41 40 42 117 140<br />
CONECT 42 41 43 79 102<br />
CONECT 43 42 44 47 80<br />
CONECT 44 39 43 81 82<br />
CONECT 45 5 19 46<br />
CONECT 46 15 45 83 141<br />
CONECT 47 43 48 84 116<br />
CONECT 48 15 30 47 85<br />
CONECT 49 28 50 86<br />
CONECT 50 25 49 103<br />
CONECT 51 52 56 106<br />
CONECT 52 51 53 54 87<br />
CONECT 53 52 88 104 128<br />
CONECT 54 52 55 89 90<br />
CONECT 55 54 57 58 91<br />
CONECT 56 25 51 92<br />
CONECT 57 55 93 105 127<br />
CONECT 58 10 55 61<br />
CONECT 59 64 94 124 125<br />
CONECT 60 8 95 96 120<br />
CONECT 61 13 58 63 144<br />
CONECT 62 13 126 142 143<br />
CONECT 63 12 61 64 97<br />
CONECT 64 18 59 63<br />
CONECT 65 19 98 122 123<br />
CONECT 66 3<br />
CONECT 67 12<br />
CONECT 68 18<br />
CONECT 69 19<br />
CONECT 70 21<br />
CONECT 71 25<br />
CONECT 72 29<br />
CONECT 73 30<br />
CONECT 74 31<br />
CONECT 75 32<br />
CONECT 76 33<br />
CONECT 77 36<br />
CONECT 78 38<br />
CONECT 79 42<br />
CONECT 80 43<br />
CONECT 81 44<br />
CONECT 82 44<br />
CONECT 83 46<br />
CONECT 84 47<br />
CONECT 85 48<br />
CONECT 86 49<br />
CONECT 87 52<br />
CONECT 88 53<br />
CONECT 89 54<br />
CONECT 90 54<br />
CONECT 91 55<br />
CONECT 92 56<br />
CONECT 93 57<br />
CONECT 94 59<br />
CONECT 95 60<br />
CONECT 96 60<br />
CONECT 97 63<br />
CONECT 98 65<br />
CONECT 99 17<br />
CONECT 100 37<br />
CONECT 101 37<br />
CONECT 102 42<br />
CONECT 103 50<br />
CONECT 104 53<br />
CONECT 105 57<br />
CONECT 106 51<br />
CONECT 107 34<br />
CONECT 108 34<br />
CONECT 109 38<br />
CONECT 110 38<br />
CONECT 111 36<br />
CONECT 112 33<br />
CONECT 113 27<br />
CONECT 114 30<br />
CONECT 115 30<br />
CONECT 116 47<br />
CONECT 117 41<br />
CONECT 118 40<br />
CONECT 119 39<br />
CONECT 120 60<br />
CONECT 121 7<br />
CONECT 122 65<br />
CONECT 123 65<br />
CONECT 124 59<br />
CONECT 125 59<br />
CONECT 126 62<br />
CONECT 127 57<br />
CONECT 128 53<br />
CONECT 129 26<br />
CONECT 130 17<br />
CONECT 131 24<br />
CONECT 132 29<br />
CONECT 133 31<br />
CONECT 134 31<br />
CONECT 135 15<br />
CONECT 136 32<br />
CONECT 137 35<br />
CONECT 138 35<br />
CONECT 139 37<br />
CONECT 140 41<br />
CONECT 141 46<br />
CONECT 142 62<br />
CONECT 143 62<br />
CONECT 144 61<br />
CONECT 145 0<br />
MASTER 0 0 0 0 0 0 0 0 145 0 145 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br><br />
6) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato; J. Am. Chem. Soc.; 115; 1993; 4419-4420 <br><br />
7) D. Romo, D. D. Johnson, L. Plamondon, T. Miwa, S. L. Schreiber; J. Org. Chem.; 57; 1992; 5060-5063 <br><br />
8) http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
9) ''How Rapamycin works'' diagram taken from http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
10) http://www.rapamycin.org/rapamycin.html<br><br />
11) ''3D structure of the binding protein, <br />
FKBP 12.6 in complex with a rapamycin molecule'' <br />
image taken from http://www.rcsb.org/pdb/explore.do?structureId=1C9H</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Retinal&diff=4267
It:Retinal
2006-10-26T14:03:59Z
<p>Qlw05: /* The role of retinal in the vision process */</p>
<hr />
<div>__toc__<br />
<br />
'''Retinal''', also known as retinaldehyde or retinene<sub>1</sub> is the most important molecule associated with vision. Retinal changes structure when it is exposed to light, essentially transferring the energy from the light it absorbs to an electrical impulse in the retina of the eye, which is then passed along the optic nerve to the central nervous system to be processed. All vision systems operate in this manner, so Retinal is resposible for all vision. Retinal is a retinine molecule that exists as two different isomers - 11-cis retinal and all-trans retinal.<br />
<br />
== Structure of Cis-Retinal ==<br />
<br />
{| class="toccolours" border="0" style="fix: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" bgcolor="lt blue"|'''2D Structure'''<br />
| align="center" bgcolor="lt blue"|'''3D Structure'''<br />
|-<br />
| [[image:Cis-RetinalSo.gif]]<br />
|<jmol><br />
<jmolApplet><br />
<size>350</size><br />
<color>white</color><br />
<script>zoom 100; bns on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
HEADER NONAME 23-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 23-Oct-06 0 NONE 4<br />
ATOM 1 O 0 -4.284 3.090 -0.370 0.00 0.00 O+0<br />
ATOM 2 C 0 -4.565 2.093 0.267 0.00 0.00 C+0<br />
ATOM 3 H 0 -5.014 2.185 1.244 0.00 0.00 H+0<br />
ATOM 4 C 0 -4.301 0.826 -0.264 0.00 0.00 C+0<br />
ATOM 5 H 0 -3.848 0.734 -1.240 0.00 0.00 H+0<br />
ATOM 6 C 0 -4.620 -0.304 0.458 0.00 0.00 C+0<br />
ATOM 7 C 0 -5.252 -0.175 1.820 0.00 0.00 C+0<br />
ATOM 8 H 0 -5.510 -1.165 2.196 0.00 0.00 H+0<br />
ATOM 9 H 0 -4.549 0.302 2.503 0.00 0.00 H+0<br />
ATOM 10 H 0 -6.155 0.431 1.745 0.00 0.00 H+0<br />
ATOM 11 C 0 -4.356 -1.571 -0.074 0.00 0.00 C+0<br />
ATOM 12 H 0 -5.156 -2.288 -0.184 0.00 0.00 H+0<br />
ATOM 13 C 0 -3.075 -1.905 -0.455 0.00 0.00 C+0<br />
ATOM 14 H 0 -2.888 -2.841 -0.961 0.00 0.00 H+0<br />
ATOM 15 C 0 -2.013 -1.030 -0.187 0.00 0.00 C+0<br />
ATOM 16 H 0 -2.209 -0.062 0.250 0.00 0.00 H+0<br />
ATOM 17 C 0 -0.732 -1.401 -0.480 0.00 0.00 C+0<br />
ATOM 18 C 0 -0.460 -2.751 -1.091 0.00 0.00 C+0<br />
ATOM 19 H 0 0.617 -2.905 -1.166 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.895 -3.529 -0.463 0.00 0.00 H+0<br />
ATOM 21 H 0 -0.903 -2.796 -2.086 0.00 0.00 H+0<br />
ATOM 22 C 0 0.332 -0.523 -0.212 0.00 0.00 C+0<br />
ATOM 23 H 0 0.148 0.407 0.306 0.00 0.00 H+0<br />
ATOM 24 C 0 1.593 -0.845 -0.603 0.00 0.00 C+0<br />
ATOM 25 H 0 1.769 -1.745 -1.174 0.00 0.00 H+0<br />
ATOM 26 C 0 2.679 0.001 -0.262 0.00 0.00 C+0<br />
ATOM 27 C 0 2.629 1.266 -0.646 0.00 0.00 C+0<br />
ATOM 28 C 0 1.416 1.729 -1.413 0.00 0.00 C+0<br />
ATOM 29 H 0 0.676 2.124 -0.718 0.00 0.00 H+0<br />
ATOM 30 H 0 1.708 2.509 -2.116 0.00 0.00 H+0<br />
ATOM 31 H 0 0.989 0.888 -1.959 0.00 0.00 H+0<br />
ATOM 32 C 0 3.711 2.266 -0.361 0.00 0.00 C+0<br />
ATOM 33 H 0 4.301 2.427 -1.263 0.00 0.00 H+0<br />
ATOM 34 H 0 3.259 3.209 -0.052 0.00 0.00 H+0<br />
ATOM 35 C 0 4.621 1.753 0.756 0.00 0.00 C+0<br />
ATOM 36 H 0 4.080 1.760 1.702 0.00 0.00 H+0<br />
ATOM 37 H 0 5.501 2.391 0.833 0.00 0.00 H+0<br />
ATOM 38 C 0 5.048 0.319 0.417 0.00 0.00 C+0<br />
ATOM 39 H 0 5.449 0.286 -0.595 0.00 0.00 H+0<br />
ATOM 40 H 0 5.809 -0.013 1.124 0.00 0.00 H+0<br />
ATOM 41 C 0 3.817 -0.587 0.519 0.00 0.00 C+0<br />
ATOM 42 C 0 3.414 -0.733 1.988 0.00 0.00 C+0<br />
ATOM 43 H 0 3.178 0.249 2.399 0.00 0.00 H+0<br />
ATOM 44 H 0 2.538 -1.377 2.062 0.00 0.00 H+0<br />
ATOM 45 H 0 4.238 -1.173 2.549 0.00 0.00 H+0<br />
ATOM 46 C 0 4.155 -1.967 -0.050 0.00 0.00 C+0<br />
ATOM 47 H 0 4.922 -2.436 0.566 0.00 0.00 H+0<br />
ATOM 48 H 0 3.260 -2.589 -0.051 0.00 0.00 H+0<br />
ATOM 49 H 0 4.524 -1.859 -1.070 0.00 0.00 H+0<br />
CONECT 1 2 0 0 0 NONE 54<br />
CONECT 2 1 3 4 0 NONE 55<br />
CONECT 4 2 5 6 0 NONE 56<br />
CONECT 6 4 7 11 0 NONE 57<br />
CONECT 7 6 8 9 10 NONE 58<br />
CONECT 11 6 12 13 0 NONE 59<br />
CONECT 13 11 14 15 0 NONE 60<br />
CONECT 15 13 16 17 0 NONE 61<br />
CONECT 17 15 18 22 0 NONE 62<br />
CONECT 18 17 19 20 21 NONE 63<br />
CONECT 22 17 23 24 0 NONE 64<br />
CONECT 24 22 25 26 0 NONE 65<br />
CONECT 26 24 41 27 0 NONE 66<br />
CONECT 27 26 28 32 0 NONE 67<br />
CONECT 28 27 29 30 31 NONE 68<br />
CONECT 32 27 33 34 35 NONE 69<br />
CONECT 35 32 36 37 38 NONE 70<br />
CONECT 38 35 39 40 41 NONE 71<br />
CONECT 41 38 26 42 46 NONE 72<br />
CONECT 42 41 43 44 45 NONE 73<br />
CONECT 46 41 47 48 49 NONE 74<br />
END NONE 75<br />
NONE 70<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|}<br />
<br />
== Properties of Cis-Retinal and Trans-Retinal ==<br />
<br />
{| class="toccolours" border="1" style="fix : right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" colspan="1" bgcolor="lt blue"|<br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Cis-Retinal''' <br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Trans-Retinal''' <br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''General properties''' <br />
|-<br />
| Chemical name<br />
| align="center"|(11Z)-retinal<br />
| align="center"|...<br />
|-<br />
| Chemical formula<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
|-<br />
| Molecular mass<br />
| align="center"|284 g/mol<br />
| align="center"|284 g/mol<br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''Physical properties'''<br />
|-<br />
| Melting point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Boiling point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Appearance<br />
| align="center"|...<br />
| align="center"|...<br />
|-<br />
| align="center" colspan="3" bgcolor="white" |'''Miscelleneous'''<br />
|-<br />
| SMILES<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C\C(C)=C\C=O)<br />
=C(C)CCC1<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C/C(C)=C/C=O)<br />
=C(C)CCC1<br />
|-<br />
|}<br />
<br />
==Structure of all-trans retinal==<br />
'''2D Structure'''<br />
<br />
[[Image:AllTransRetinal.gif]]<br />
<br />
<br />
<br />
==The role of retinal in the vision process==<br />
<br />
The molecule that takes part in the vision process is rhodopsin which consists of 11-cis retinal and protein opsin. Retinal is a Vitamin A derivative. When there is no light present the 11-cis retinal has a bent configuration and is attached to the retinal molecule in a stable arrangement. When light strikes the retina, the retinal molecule absorbs a photon into one of the pi-bonds between the 11th and 12th carbon atoms, hence the 11 cis retinal is transfformed into the all trans retinal.<br />
<br />
[[Image:RetinalConversion.png]]<br />
<br>Compound A 3D Picture<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>Black</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY CRETAL01<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 13.180 7.499 17.803 90.00 95.66 90.00 P 21/n 4<br />
ATOM 1 C1 UNK 0 1 3.279 5.402 15.975 1.00 0.00<br />
ATOM 2 C2 UNK 0 1 4.046 6.337 15.055 1.00 0.00<br />
ATOM 3 C3 UNK 0 1 3.501 7.731 15.036 1.00 0.00<br />
ATOM 4 C4 UNK 0 1 2.048 7.716 14.547 1.00 0.00<br />
ATOM 5 C5 UNK 0 1 1.242 6.570 15.071 1.00 0.00<br />
ATOM 6 C6 UNK 0 1 1.742 5.525 15.720 1.00 0.00<br />
ATOM 7 C7 UNK 0 1 0.960 4.412 16.249 1.00 0.00<br />
ATOM 8 C8 UNK 0 1 -0.096 3.785 15.688 1.00 0.00<br />
ATOM 9 C9 UNK 0 1 -0.891 2.748 16.260 1.00 0.00<br />
ATOM 10 C10 UNK 0 1 -2.039 2.359 15.656 1.00 0.00<br />
ATOM 11 C11 UNK 0 1 -2.995 1.432 16.171 1.00 0.00<br />
ATOM 12 C12 UNK 0 1 -4.118 0.952 15.603 1.00 0.00<br />
ATOM 13 C13 UNK 0 1 -4.579 1.155 14.210 1.00 0.00<br />
ATOM 14 C14 UNK 0 1 -3.772 1.162 13.168 1.00 0.00<br />
ATOM 15 C15 UNK 0 1 -4.144 1.290 11.748 1.00 0.00<br />
ATOM 16 O1 UNK 0 1 -3.417 1.200 10.832 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 -0.251 6.757 14.825 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 3.537 5.722 17.465 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 3.755 3.989 15.704 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 -0.446 2.130 17.555 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 -6.097 1.275 14.125 1.00 0.00<br />
ATOM 22 H1 UNK 0 1 4.961 6.299 15.236 1.00 0.00<br />
ATOM 23 H2 UNK 0 1 4.033 6.074 13.960 1.00 0.00<br />
ATOM 24 H3 UNK 0 1 3.361 8.099 16.086 1.00 0.00<br />
ATOM 25 H4 UNK 0 1 4.112 8.346 14.368 1.00 0.00<br />
ATOM 26 H5 UNK 0 1 1.613 8.609 14.846 1.00 0.00<br />
ATOM 27 H6 UNK 0 1 2.096 8.271 13.429 1.00 0.00<br />
ATOM 28 H7 UNK 0 1 1.167 4.027 17.220 1.00 0.00<br />
ATOM 29 H8 UNK 0 1 -0.283 4.132 14.828 1.00 0.00<br />
ATOM 30 H9 UNK 0 1 -2.166 2.700 14.811 1.00 0.00<br />
ATOM 31 H10 UNK 0 1 -2.959 1.140 17.220 1.00 0.00<br />
ATOM 32 H11 UNK 0 1 -4.766 0.337 16.175 1.00 0.00<br />
ATOM 33 H12 UNK 0 1 -2.863 1.012 13.199 1.00 0.00<br />
ATOM 34 H13 UNK 0 1 -5.051 1.500 11.604 1.00 0.00<br />
ATOM 35 H14 UNK 0 1 -0.500 7.641 14.882 1.00 0.00<br />
ATOM 36 H15 UNK 0 1 -0.354 6.404 13.677 1.00 0.00<br />
ATOM 37 H16 UNK 0 1 -0.828 6.374 15.537 1.00 0.00<br />
ATOM 38 H17 UNK 0 1 4.443 5.482 17.539 1.00 0.00<br />
ATOM 39 H18 UNK 0 1 3.171 6.749 17.876 1.00 0.00<br />
ATOM 40 H19 UNK 0 1 2.971 5.092 18.159 1.00 0.00<br />
ATOM 41 H20 UNK 0 1 3.359 3.330 16.246 1.00 0.00<br />
ATOM 42 H21 UNK 0 1 3.564 3.712 14.704 1.00 0.00<br />
ATOM 43 H22 UNK 0 1 4.832 3.967 15.608 1.00 0.00<br />
ATOM 44 H23 UNK 0 1 0.526 2.025 17.433 1.00 0.00<br />
ATOM 45 H24 UNK 0 1 -0.489 2.700 18.230 1.00 0.00<br />
ATOM 46 H25 UNK 0 1 -1.006 1.387 18.000 1.00 0.00<br />
ATOM 47 H26 UNK 0 1 -6.646 0.300 14.793 1.00 0.00<br />
ATOM 48 H27 UNK 0 1 -6.440 2.100 14.580 1.00 0.00<br />
ATOM 49 H28 UNK 0 1 -6.271 1.320 13.269 1.00 0.00<br />
CONECT 1 2 6 18 19<br />
CONECT 2 1 3 22 23<br />
CONECT 3 2 4 24 25<br />
CONECT 4 3 5 26 27<br />
CONECT 5 4 6 17<br />
CONECT 6 1 5 7<br />
CONECT 7 6 8 28<br />
CONECT 8 7 9 29<br />
CONECT 9 8 10 20<br />
CONECT 10 9 11 30<br />
CONECT 11 10 12 31<br />
CONECT 12 11 13 32<br />
CONECT 13 12 14 21<br />
CONECT 14 13 15 33<br />
CONECT 15 14 16 34<br />
CONECT 16 15<br />
CONECT 17 5 35 36 37<br />
CONECT 18 1 38 39 40<br />
CONECT 19 1 41 42 43<br />
CONECT 20 9 44 45 46<br />
CONECT 21 13 47 48 49<br />
CONECT 22 2<br />
CONECT 23 2<br />
CONECT 24 3<br />
CONECT 25 3<br />
CONECT 26 4<br />
CONECT 27 4<br />
CONECT 28 7<br />
CONECT 29 8<br />
CONECT 30 10<br />
CONECT 31 11<br />
CONECT 32 12<br />
CONECT 33 14<br />
CONECT 34 15<br />
CONECT 35 17<br />
CONECT 36 17<br />
CONECT 37 17<br />
CONECT 38 18<br />
CONECT 39 18<br />
CONECT 40 18<br />
CONECT 41 19<br />
CONECT 42 19<br />
CONECT 43 19<br />
CONECT 44 20<br />
CONECT 45 20<br />
CONECT 46 20<br />
CONECT 47 21<br />
CONECT 48 21<br />
CONECT 49 21<br />
MASTER 0 0 0 0 0 0 0 0 49 0 49 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
Compound B 3D picture<br />
<jmol><br />
<jmolApplet><br />
<size>300</size><br />
<color>black</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY TRETAL03<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 14.956 8.277 15.291 90.00 104.92 90.00 P 21/n 4<br />
ATOM 1 O1 UNK 0 1 9.309 3.852 9.139 1.00 0.00<br />
ATOM 2 C1 UNK 0 1 -1.723 -0.739 4.047 1.00 0.00<br />
ATOM 3 C2 UNK 0 1 -0.452 -1.316 3.444 1.00 0.00<br />
ATOM 4 C3 UNK 0 1 -2.519 -1.832 4.761 1.00 0.00<br />
ATOM 5 C4 UNK 0 1 -2.460 -0.197 2.791 1.00 0.00<br />
ATOM 6 C5 UNK 0 1 -3.484 0.764 3.073 1.00 0.00<br />
ATOM 7 C6 UNK 0 1 -3.039 1.904 3.908 1.00 0.00<br />
ATOM 8 C7 UNK 0 1 -2.002 1.579 4.954 1.00 0.00<br />
ATOM 9 C8 UNK 0 1 -1.767 2.692 5.929 1.00 0.00<br />
ATOM 10 C9 UNK 0 1 -1.402 0.397 5.000 1.00 0.00<br />
ATOM 11 C10 UNK 0 1 -0.360 0.092 6.017 1.00 0.00<br />
ATOM 12 C11 UNK 0 1 0.764 0.756 6.175 1.00 0.00<br />
ATOM 13 C12 UNK 0 1 1.826 0.493 7.151 1.00 0.00<br />
ATOM 14 C13 UNK 0 1 1.604 -0.603 8.138 1.00 0.00<br />
ATOM 15 C14 UNK 0 1 2.930 1.234 7.109 1.00 0.00<br />
ATOM 16 C15 UNK 0 1 4.081 1.142 7.980 1.00 0.00<br />
ATOM 17 C16 UNK 0 1 5.145 1.932 7.893 1.00 0.00<br />
ATOM 18 C17 UNK 0 1 6.289 1.962 8.796 1.00 0.00<br />
ATOM 19 C18 UNK 0 1 6.288 1.002 9.940 1.00 0.00<br />
ATOM 20 C19 UNK 0 1 7.263 2.851 8.564 1.00 0.00<br />
ATOM 21 C20 UNK 0 1 8.452 3.036 9.396 1.00 0.00<br />
CONECT 1 21<br />
CONECT 2 3 4 5 10<br />
CONECT 3 2<br />
CONECT 4 2<br />
CONECT 5 2 6<br />
CONECT 6 5 7<br />
CONECT 7 6 8<br />
CONECT 8 7 9 10<br />
CONECT 9 8<br />
CONECT 10 2 8 11<br />
CONECT 11 10 12<br />
CONECT 12 11 13<br />
CONECT 13 12 14 15<br />
CONECT 14 13<br />
CONECT 15 13 16<br />
CONECT 16 15 17<br />
CONECT 17 16 18<br />
CONECT 18 17 19 20<br />
CONECT 19 18<br />
CONECT 20 18 21<br />
CONECT 21 1 20<br />
MASTER 0 0 0 0 0 0 0 0 21 0 21 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
==Synthesis of Rhodopsin==<br />
[[Image:Synthesis_of_rhodopsin.gif]]<br />
<br />
==Effects of Bunazosin on ocular circulation and retinal neuronal damage==<br />
<br />
By applying bunazosin hydrochloride into a healthy humans, it increases the blood velocity in the optic nerve head(ONH),retina and choroid, without changing either heart rate and blood pressure dramaticallt. This drup also applied to rabit and rat which gave positive results. These shows that bunazosin hydrochloride have improvement effect both in the ocular circulation and a direct neuroprotective effct. Therefore, it may be useful to use bunazosin hydrochloride as a therapeutic drug against retinal diseases which is associated with the ocular circulation.<br />
<br />
<br />
<br />
== References ==<br />
<br />
*Beilstein Data: Copyright (c) 1988-2006, Beilstein institut zur Foerderung der Chemischen Wissenschaften licensed to Beilstein GmBH and MDL information systems GmbH<br />
<br />
*1.Chang, Raymond (1998). Chemistry, 6th Ed.. New York: McGraw Hill. ISBN 0-07-115221-0. <br />
*2. Feynman, Richard (1985). QED - The Strange Theory of Light and Matter. Princeton, New Jersey: Princeton University Press. ISBN 0691024170.<br />
*3.Hara, Hideaki / Ichikawa, Masaki / Oku, Hidehiro / Shimazawa, Masamitsu / Araie, Makoto, Cardiovascular drug reviews, Apr 2005</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4226
It:Rapamycin
2006-10-26T13:34:14Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:Rapamycin.gif|50|2D structure of Rapamycin|50]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
The rapamycin is thought to target the proteins <sup>8</sup>:<br />
(1) 70-kD S6 protein kinase p70<sup>S6K</sup><br />
(2) Eukaryotic initiation factor eIF-4F<br />
(3) G1-controlling cyclin-dependent kinase (cdk) proteins <br />
(4) Kinase inhibitory protein Kip1 (p27<sup>kip</sup>), which blocks cell progression to the S phase.<br />
<br />
The diagram below shows how the mechanism steps of how rapamycin works:<br />
<br />
'''How Rapamycin works'''<br />
[[Image:mechanism.gif]]<br />
<br />
''Note:''<br />
SRL = Sirolimus (rapamycin)<br />
mTOR = mammalian target of rapamycin<br />
CsA = Cyclosporine<br />
PTKs = protein tyrosine kinases<br />
p34<sup>cdc2</sup> = a kinase<br />
<br />
Below is the 3D structure of the binding protein, FKBP 12.6 in complex with a rapamycin molecule: <br />
<br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Thu Oct 26 13:37:31 GMT Standard Time 2006<br />
CRYST1 45.696 49.288 51.694 90.00 90.00 90.00 P212121<br />
ATOM 1 N GLY A 1 -6.981 2.196 -6.695 1.00 0.00 <br />
ATOM 2 CA GLY A 1 -8.065 1.703 -5.797 1.00 0.00 <br />
ATOM 3 C GLY A 1 -9.417 2.193 -6.277 1.00 0.00 <br />
ATOM 4 O GLY A 1 -9.620 2.391 -7.474 1.00 0.00 <br />
ATOM 5 N VAL A 2 -10.341 2.395 -5.345 1.00 0.00 <br />
ATOM 6 CA VAL A 2 -11.672 2.874 -5.688 1.00 0.00 <br />
ATOM 7 C VAL A 2 -11.896 4.253 -5.093 1.00 0.00 <br />
ATOM 8 O VAL A 2 -11.650 4.467 -3.906 1.00 0.00 <br />
ATOM 9 CB VAL A 2 -12.775 1.964 -5.119 1.00 0.00 <br />
ATOM 10 CG1 VAL A 2 -14.094 2.249 -5.822 1.00 0.00 <br />
ATOM 11 CG2 VAL A 2 -12.376 0.517 -5.254 1.00 0.00 <br />
ATOM 12 N GLU A 3 -12.355 5.183 -5.923 1.00 0.00 <br />
ATOM 13 CA GLU A 3 -12.654 6.535 -5.471 1.00 0.00 <br />
ATOM 14 C GLU A 3 -14.163 6.708 -5.554 1.00 0.00 <br />
ATOM 15 O GLU A 3 -14.802 6.200 -6.474 1.00 0.00 <br />
ATOM 16 CB GLU A 3 -11.955 7.572 -6.348 1.00 0.00 <br />
ATOM 17 CG GLU A 3 -10.439 7.498 -6.286 1.00 0.00 <br />
ATOM 18 CD GLU A 3 -9.773 8.693 -6.944 1.00 0.00 <br />
ATOM 19 OE1 GLU A 3 -10.120 9.004 -8.106 1.00 0.00 <br />
ATOM 20 OE2 GLU A 3 -8.902 9.321 -6.299 1.00 0.00 <br />
ATOM 21 N ILE A 4 -14.724 7.428 -4.590 1.00 0.00 <br />
ATOM 22 CA ILE A 4 -16.160 7.645 -4.517 1.00 0.00 <br />
ATOM 23 C ILE A 4 -16.539 9.118 -4.648 1.00 0.00 <br />
ATOM 24 O ILE A 4 -15.943 9.977 -4.004 1.00 0.00 <br />
ATOM 25 CB ILE A 4 -16.728 7.152 -3.150 1.00 0.00 <br />
ATOM 26 CG1 ILE A 4 -16.327 5.697 -2.890 1.00 0.00 <br />
ATOM 27 CG2 ILE A 4 -18.232 7.308 -3.120 1.00 0.00 <br />
ATOM 28 CD1 ILE A 4 -16.872 4.708 -3.892 1.00 0.00 <br />
ATOM 29 N GLU A 5 -17.527 9.393 -5.494 1.00 0.00 <br />
ATOM 30 CA GLU A 5 -18.054 10.744 -5.669 1.00 0.00 <br />
ATOM 31 C GLU A 5 -19.552 10.561 -5.505 1.00 0.00 <br />
ATOM 32 O GLU A 5 -20.210 9.962 -6.357 1.00 0.00 <br />
ATOM 33 CB GLU A 5 -17.748 11.307 -7.060 1.00 0.00 <br />
ATOM 34 CG GLU A 5 -16.281 11.588 -7.305 1.00 0.00 <br />
ATOM 35 CD GLU A 5 -16.027 12.152 -8.688 1.00 0.00 <br />
ATOM 36 OE1 GLU A 5 -16.467 13.290 -8.959 1.00 0.00 <br />
ATOM 37 OE2 GLU A 5 -15.390 11.452 -9.505 1.00 0.00 <br />
ATOM 38 N THR A 6 -20.086 11.064 -4.401 1.00 0.00 <br />
ATOM 39 CA THR A 6 -21.503 10.918 -4.115 1.00 0.00 <br />
ATOM 40 C THR A 6 -22.435 11.594 -5.113 1.00 0.00 <br />
ATOM 41 O THR A 6 -22.225 12.741 -5.517 1.00 0.00 <br />
ATOM 42 CB THR A 6 -21.819 11.427 -2.699 1.00 0.00 <br />
ATOM 43 OG1 THR A 6 -21.153 10.595 -1.743 1.00 0.00 <br />
ATOM 44 CG2 THR A 6 -23.321 11.402 -2.440 1.00 0.00 <br />
ATOM 45 N ILE A 7 -23.461 10.853 -5.514 1.00 0.00 <br />
ATOM 46 CA ILE A 7 -24.471 11.341 -6.443 1.00 0.00 <br />
ATOM 47 C ILE A 7 -25.656 11.812 -5.601 1.00 0.00 <br />
ATOM 48 O ILE A 7 -26.213 12.891 -5.818 1.00 0.00 <br />
ATOM 49 CB ILE A 7 -24.909 10.212 -7.401 1.00 0.00 <br />
ATOM 50 CG1 ILE A 7 -23.758 9.896 -8.365 1.00 0.00 <br />
ATOM 51 CG2 ILE A 7 -26.173 10.614 -8.163 1.00 0.00 <br />
ATOM 52 CD1 ILE A 7 -24.015 8.709 -9.281 1.00 0.00 <br />
ATOM 53 N SER A 8 -26.033 10.977 -4.639 1.00 0.00 <br />
ATOM 54 CA SER A 8 -27.119 11.267 -3.707 1.00 0.00 <br />
ATOM 55 C SER A 8 -26.659 10.688 -2.380 1.00 0.00 <br />
ATOM 56 O SER A 8 -26.206 9.549 -2.323 1.00 0.00 <br />
ATOM 57 CB SER A 8 -28.422 10.596 -4.144 1.00 0.00 <br />
ATOM 58 OG SER A 8 -29.022 11.290 -5.223 1.00 0.00 <br />
ATOM 59 N PRO A 9 -26.773 11.462 -1.292 1.00 0.00 <br />
ATOM 60 CA PRO A 9 -26.339 10.972 0.020 1.00 0.00 <br />
ATOM 61 C PRO A 9 -27.220 9.882 0.618 1.00 0.00 <br />
ATOM 62 O PRO A 9 -28.409 9.801 0.324 1.00 0.00 <br />
ATOM 63 CB PRO A 9 -26.321 12.244 0.868 1.00 0.00 <br />
ATOM 64 CG PRO A 9 -27.477 13.024 0.300 1.00 0.00 <br />
ATOM 65 CD PRO A 9 -27.298 12.837 -1.201 1.00 0.00 <br />
ATOM 66 N GLY A 10 -26.617 9.034 1.446 1.00 0.00 <br />
ATOM 67 CA GLY A 10 -27.365 7.973 2.098 1.00 0.00 <br />
ATOM 68 C GLY A 10 -27.791 8.483 3.463 1.00 0.00 <br />
ATOM 69 O GLY A 10 -27.748 9.688 3.707 1.00 0.00 <br />
ATOM 70 N ASP A 11 -28.198 7.595 4.363 1.00 0.00 <br />
ATOM 71 CA ASP A 11 -28.605 8.063 5.682 1.00 0.00 <br />
ATOM 72 C ASP A 11 -27.363 8.404 6.509 1.00 0.00 <br />
ATOM 73 O ASP A 11 -27.462 8.997 7.583 1.00 0.00 <br />
ATOM 74 CB ASP A 11 -29.469 7.014 6.394 1.00 0.00 <br />
ATOM 75 CG ASP A 11 -28.717 5.729 6.695 1.00 0.00 <br />
ATOM 76 OD1 ASP A 11 -27.485 5.676 6.484 1.00 0.00 <br />
ATOM 77 OD2 ASP A 11 -29.373 4.771 7.158 1.00 0.00 <br />
ATOM 78 N GLY A 12 -26.196 8.029 5.990 1.00 0.00 <br />
ATOM 79 CA GLY A 12 -24.941 8.314 6.664 1.00 0.00 <br />
ATOM 80 C GLY A 12 -24.631 7.519 7.920 1.00 0.00 <br />
ATOM 81 O GLY A 12 -23.743 7.898 8.690 1.00 0.00 <br />
ATOM 82 N ARG A 13 -25.335 6.415 8.137 1.00 0.00 <br />
ATOM 83 CA ARG A 13 -25.084 5.619 9.329 1.00 0.00 <br />
ATOM 84 C ARG A 13 -25.326 4.126 9.156 1.00 0.00 <br />
ATOM 85 O ARG A 13 -24.781 3.320 9.907 1.00 0.00 <br />
ATOM 86 CB ARG A 13 -25.919 6.156 10.498 1.00 0.00 <br />
ATOM 87 CG ARG A 13 -27.396 6.326 10.197 1.00 0.00 <br />
ATOM 88 CD ARG A 13 -28.075 7.146 11.295 1.00 0.00 <br />
ATOM 89 NE ARG A 13 -29.469 7.446 10.981 1.00 0.00 <br />
ATOM 90 CZ ARG A 13 -30.430 6.533 10.895 1.00 0.00 <br />
ATOM 91 NH1 ARG A 13 -30.152 5.252 11.103 1.00 0.00 <br />
ATOM 92 NH2 ARG A 13 -31.669 6.897 10.593 1.00 0.00 <br />
ATOM 93 N THR A 14 -26.126 3.755 8.163 1.00 0.00 <br />
ATOM 94 CA THR A 14 -26.420 2.346 7.925 1.00 0.00 <br />
ATOM 95 C THR A 14 -25.571 1.781 6.791 1.00 0.00 <br />
ATOM 96 O THR A 14 -25.933 1.895 5.619 1.00 0.00 <br />
ATOM 97 CB THR A 14 -27.907 2.141 7.586 1.00 0.00 <br />
ATOM 98 OG1 THR A 14 -28.718 2.756 8.599 1.00 0.00 <br />
ATOM 99 CG2 THR A 14 -28.236 0.657 7.519 1.00 0.00 <br />
ATOM 100 N PHE A 15 -24.445 1.166 7.150 1.00 0.00 <br />
ATOM 101 CA PHE A 15 -23.527 0.588 6.174 1.00 0.00 <br />
ATOM 102 C PHE A 15 -23.654 -0.930 6.104 1.00 0.00 <br />
ATOM 103 O PHE A 15 -24.151 -1.569 7.035 1.00 0.00 <br />
ATOM 104 CB PHE A 15 -22.074 0.944 6.521 1.00 0.00 <br />
ATOM 105 CG PHE A 15 -21.800 2.422 6.558 1.00 0.00 <br />
ATOM 106 CD1 PHE A 15 -22.182 3.186 7.656 1.00 0.00 <br />
ATOM 107 CD2 PHE A 15 -21.176 3.052 5.488 1.00 0.00 <br />
ATOM 108 CE1 PHE A 15 -21.943 4.564 7.689 1.00 0.00 <br />
ATOM 109 CE2 PHE A 15 -20.933 4.429 5.508 1.00 0.00 <br />
ATOM 110 CZ PHE A 15 -21.318 5.184 6.614 1.00 0.00 <br />
ATOM 111 N PRO A 16 -23.198 -1.529 4.994 1.00 0.00 <br />
ATOM 112 CA PRO A 16 -23.272 -2.984 4.832 1.00 0.00 <br />
ATOM 113 C PRO A 16 -22.464 -3.715 5.904 1.00 0.00 <br />
ATOM 114 O PRO A 16 -21.291 -3.410 6.120 1.00 0.00 <br />
ATOM 115 CB PRO A 16 -22.694 -3.205 3.433 1.00 0.00 <br />
ATOM 116 CG PRO A 16 -23.072 -1.940 2.713 1.00 0.00 <br />
ATOM 117 CD PRO A 16 -22.744 -0.887 3.748 1.00 0.00 <br />
ATOM 118 N LYS A 17 -23.102 -4.668 6.578 1.00 0.00 <br />
ATOM 119 CA LYS A 17 -22.435 -5.451 7.614 1.00 0.00 <br />
ATOM 120 C LYS A 17 -21.978 -6.781 7.019 1.00 0.00 <br />
ATOM 121 O LYS A 17 -22.447 -7.190 5.959 1.00 0.00 <br />
ATOM 122 CB LYS A 17 -23.385 -5.729 8.782 1.00 0.00 <br />
ATOM 123 CG LYS A 17 -23.891 -4.500 9.515 1.00 0.00 <br />
ATOM 124 CD LYS A 17 -24.763 -4.914 10.696 1.00 0.00 <br />
ATOM 125 CE LYS A 17 -25.272 -3.707 11.472 1.00 0.00 <br />
ATOM 126 NZ LYS A 17 -26.068 -4.106 12.674 1.00 0.00 <br />
ATOM 127 N LYS A 18 -21.072 -7.460 7.713 1.00 0.00 <br />
ATOM 128 CA LYS A 18 -20.565 -8.745 7.243 1.00 0.00 <br />
ATOM 129 C LYS A 18 -21.705 -9.742 7.046 1.00 0.00 <br />
ATOM 130 O LYS A 18 -22.583 -9.871 7.896 1.00 0.00 <br />
ATOM 131 CB LYS A 18 -19.559 -9.310 8.247 1.00 0.00 <br />
ATOM 132 CG LYS A 18 -18.379 -8.395 8.523 1.00 0.00 <br />
ATOM 133 CD LYS A 18 -17.434 -9.010 9.547 1.00 0.00 <br />
ATOM 134 CE LYS A 18 -16.263 -8.085 9.851 1.00 0.00 <br />
ATOM 135 NZ LYS A 18 -15.335 -8.691 10.844 1.00 0.00 <br />
ATOM 136 N GLY A 19 -21.692 -10.435 5.912 1.00 0.00 <br />
ATOM 137 CA GLY A 19 -22.726 -11.418 5.637 1.00 0.00 <br />
ATOM 138 C GLY A 19 -24.002 -10.886 5.009 1.00 0.00 <br />
ATOM 139 O GLY A 19 -24.752 -11.645 4.390 1.00 0.00 <br />
ATOM 140 N GLN A 20 -24.262 -9.590 5.165 1.00 0.00 <br />
ATOM 141 CA GLN A 20 -25.464 -8.992 4.596 1.00 0.00 <br />
ATOM 142 C GLN A 20 -25.453 -9.062 3.079 1.00 0.00 <br />
ATOM 143 O GLN A 20 -24.400 -9.216 2.457 1.00 0.00 <br />
ATOM 144 CB GLN A 20 -25.602 -7.527 5.016 1.00 0.00 <br />
ATOM 145 CG GLN A 20 -26.018 -7.319 6.456 1.00 0.00 <br />
ATOM 146 CD GLN A 20 -26.535 -5.914 6.703 1.00 0.00 <br />
ATOM 147 OE1 GLN A 20 -25.795 -4.937 6.592 1.00 0.00 <br />
ATOM 148 NE2 GLN A 20 -27.818 -5.806 7.030 1.00 0.00 <br />
ATOM 149 N THR A 21 -26.637 -8.950 2.490 1.00 0.00 <br />
ATOM 150 CA THR A 21 -26.773 -8.978 1.043 1.00 0.00 <br />
ATOM 151 C THR A 21 -27.114 -7.571 0.582 1.00 0.00 <br />
ATOM 152 O THR A 21 -28.130 -7.004 0.990 1.00 0.00 <br />
ATOM 153 CB THR A 21 -27.896 -9.934 0.592 1.00 0.00 <br />
ATOM 154 OG1 THR A 21 -27.606 -11.263 1.044 1.00 0.00 <br />
ATOM 155 CG2 THR A 21 -28.009 -9.935 -0.922 1.00 0.00 <br />
ATOM 156 N CYS A 22 -26.250 -7.002 -0.251 1.00 0.00 <br />
ATOM 157 CA CYS A 22 -26.479 -5.662 -0.765 1.00 0.00 <br />
ATOM 158 C CYS A 22 -27.405 -5.709 -1.970 1.00 0.00 <br />
ATOM 159 O CYS A 22 -27.232 -6.537 -2.866 1.00 0.00 <br />
ATOM 160 CB CYS A 22 -25.155 -5.012 -1.172 1.00 0.00 <br />
ATOM 161 SG CYS A 22 -24.056 -4.617 0.206 1.00 0.00 <br />
ATOM 162 N VAL A 23 -28.405 -4.835 -1.972 1.00 0.00 <br />
ATOM 163 CA VAL A 23 -29.329 -4.740 -3.093 1.00 0.00 <br />
ATOM 164 C VAL A 23 -28.961 -3.414 -3.736 1.00 0.00 <br />
ATOM 165 O VAL A 23 -29.121 -2.349 -3.137 1.00 0.00 <br />
ATOM 166 CB VAL A 23 -30.798 -4.711 -2.640 1.00 0.00 <br />
ATOM 167 CG1 VAL A 23 -31.710 -4.703 -3.861 1.00 0.00 <br />
ATOM 168 CG2 VAL A 23 -31.097 -5.921 -1.758 1.00 0.00 <br />
ATOM 169 N VAL A 24 -28.458 -3.489 -4.958 1.00 0.00 <br />
ATOM 170 CA VAL A 24 -28.003 -2.305 -5.665 1.00 0.00 <br />
ATOM 171 C VAL A 24 -28.488 -2.194 -7.105 1.00 0.00 <br />
ATOM 172 O VAL A 24 -28.914 -3.174 -7.716 1.00 0.00 <br />
ATOM 173 CB VAL A 24 -26.449 -2.289 -5.700 1.00 0.00 <br />
ATOM 174 CG1 VAL A 24 -25.945 -1.234 -6.669 1.00 0.00 <br />
ATOM 175 CG2 VAL A 24 -25.897 -2.045 -4.307 1.00 0.00 <br />
ATOM 176 N HIS A 25 -28.430 -0.973 -7.624 1.00 0.00 <br />
ATOM 177 CA HIS A 25 -28.737 -0.711 -9.015 1.00 0.00 <br />
ATOM 178 C HIS A 25 -27.410 -0.147 -9.512 1.00 0.00 <br />
ATOM 179 O HIS A 25 -26.775 0.644 -8.817 1.00 0.00 <br />
ATOM 180 CB HIS A 25 -29.841 0.328 -9.171 1.00 0.00 <br />
ATOM 181 CG HIS A 25 -31.102 -0.227 -9.753 1.00 0.00 <br />
ATOM 182 ND1 HIS A 25 -31.106 -1.070 -10.844 1.00 0.00 <br />
ATOM 183 CD2 HIS A 25 -32.399 -0.061 -9.401 1.00 0.00 <br />
ATOM 184 CE1 HIS A 25 -32.350 -1.399 -11.138 1.00 0.00 <br />
ATOM 185 NE2 HIS A 25 -33.154 -0.801 -10.278 1.00 0.00 <br />
ATOM 186 N TYR A 26 -26.967 -0.558 -10.691 1.00 0.00 <br />
ATOM 187 CA TYR A 26 -25.700 -0.054 -11.189 1.00 0.00 <br />
ATOM 188 C TYR A 26 -25.663 0.063 -12.704 1.00 0.00 <br />
ATOM 189 O TYR A 26 -26.477 -0.525 -13.415 1.00 0.00 <br />
ATOM 190 CB TYR A 26 -24.557 -0.970 -10.723 1.00 0.00 <br />
ATOM 191 CG TYR A 26 -24.487 -2.281 -11.480 1.00 0.00 <br />
ATOM 192 CD1 TYR A 26 -23.818 -2.367 -12.703 1.00 0.00 <br />
ATOM 193 CD2 TYR A 26 -25.132 -3.423 -11.002 1.00 0.00 <br />
ATOM 194 CE1 TYR A 26 -23.791 -3.555 -13.431 1.00 0.00 <br />
ATOM 195 CE2 TYR A 26 -25.118 -4.617 -11.726 1.00 0.00 <br />
ATOM 196 CZ TYR A 26 -24.445 -4.673 -12.942 1.00 0.00 <br />
ATOM 197 OH TYR A 26 -24.434 -5.841 -13.671 1.00 0.00 <br />
ATOM 198 N THR A 27 -24.697 0.840 -13.174 1.00 0.00 <br />
ATOM 199 CA THR A 27 -24.449 1.055 -14.587 1.00 0.00 <br />
ATOM 200 C THR A 27 -22.928 1.057 -14.665 1.00 0.00 <br />
ATOM 201 O THR A 27 -22.264 1.819 -13.956 1.00 0.00 <br />
ATOM 202 CB THR A 27 -24.992 2.416 -15.072 1.00 0.00 <br />
ATOM 203 OG1 THR A 27 -26.420 2.441 -14.928 1.00 0.00 <br />
ATOM 204 CG2 THR A 27 -24.624 2.646 -16.535 1.00 0.00 <br />
ATOM 205 N GLY A 28 -22.382 0.180 -15.501 1.00 0.00 <br />
ATOM 206 CA GLY A 28 -20.939 0.086 -15.638 1.00 0.00 <br />
ATOM 207 C GLY A 28 -20.472 0.667 -16.951 1.00 0.00 <br />
ATOM 208 O GLY A 28 -21.100 0.468 -17.994 1.00 0.00 <br />
ATOM 209 N MET A 29 -19.352 1.371 -16.908 1.00 0.00 <br />
ATOM 210 CA MET A 29 -18.826 2.009 -18.101 1.00 0.00 <br />
ATOM 211 C MET A 29 -17.303 2.036 -18.084 1.00 0.00 <br />
ATOM 212 O MET A 29 -16.690 2.198 -17.028 1.00 0.00 <br />
ATOM 213 CB MET A 29 -19.385 3.432 -18.163 1.00 0.00 <br />
ATOM 214 CG MET A 29 -18.848 4.325 -19.251 1.00 0.00 <br />
ATOM 215 SD MET A 29 -19.532 5.992 -19.016 1.00 0.00 <br />
ATOM 216 CE MET A 29 -18.323 6.720 -17.930 1.00 0.00 <br />
ATOM 217 N LEU A 30 -16.690 1.861 -19.248 1.00 0.00 <br />
ATOM 218 CA LEU A 30 -15.235 1.913 -19.343 1.00 0.00 <br />
ATOM 219 C LEU A 30 -14.853 3.387 -19.268 1.00 0.00 <br />
ATOM 220 O LEU A 30 -15.529 4.229 -19.857 1.00 0.00 <br />
ATOM 221 CB LEU A 30 -14.762 1.331 -20.679 1.00 0.00 <br />
ATOM 222 CG LEU A 30 -15.062 -0.143 -20.933 1.00 0.00 <br />
ATOM 223 CD1 LEU A 30 -14.700 -0.502 -22.371 1.00 0.00 <br />
ATOM 224 CD2 LEU A 30 -14.275 -0.990 -19.947 1.00 0.00 <br />
ATOM 225 N GLN A 31 -13.789 3.714 -18.543 1.00 0.00 <br />
ATOM 226 CA GLN A 31 -13.381 5.111 -18.432 1.00 0.00 <br />
ATOM 227 C GLN A 31 -13.116 5.621 -19.841 1.00 0.00 <br />
ATOM 228 O GLN A 31 -12.319 5.033 -20.568 1.00 0.00 <br />
ATOM 229 CB GLN A 31 -12.107 5.249 -17.595 1.00 0.00 <br />
ATOM 230 CG GLN A 31 -11.789 6.685 -17.216 1.00 0.00 <br />
ATOM 231 CD GLN A 31 -10.349 6.885 -16.801 1.00 0.00 <br />
ATOM 232 OE1 GLN A 31 -9.782 6.078 -16.073 1.00 0.00 <br />
ATOM 233 NE2 GLN A 31 -9.755 7.990 -17.249 1.00 0.00 <br />
ATOM 234 N ASN A 32 -13.784 6.706 -20.227 1.00 0.00 <br />
ATOM 235 CA ASN A 32 -13.610 7.268 -21.563 1.00 0.00 <br />
ATOM 236 C ASN A 32 -13.988 6.222 -22.620 1.00 0.00 <br />
ATOM 237 O ASN A 32 -13.457 6.218 -23.730 1.00 0.00 <br />
ATOM 238 CB ASN A 32 -12.156 7.717 -21.757 1.00 0.00 <br />
ATOM 239 CG ASN A 32 -11.724 8.764 -20.736 1.00 0.00 <br />
ATOM 240 OD1 ASN A 32 -10.536 8.899 -20.437 1.00 0.00 <br />
ATOM 241 ND2 ASN A 32 -12.689 9.514 -20.206 1.00 0.00 <br />
ATOM 242 N GLY A 33 -14.907 5.332 -22.262 1.00 0.00 <br />
ATOM 243 CA GLY A 33 -15.348 4.299 -23.183 1.00 0.00 <br />
ATOM 244 C GLY A 33 -16.858 4.153 -23.140 1.00 0.00 <br />
ATOM 245 O GLY A 33 -17.566 5.050 -22.680 1.00 0.00 <br />
ATOM 246 N LYS A 34 -17.356 3.013 -23.602 1.00 0.00 <br />
ATOM 247 CA LYS A 34 -18.790 2.760 -23.629 1.00 0.00 <br />
ATOM 248 C LYS A 34 -19.330 2.102 -22.363 1.00 0.00 <br />
ATOM 249 O LYS A 34 -18.587 1.494 -21.588 1.00 0.00 <br />
ATOM 250 CB LYS A 34 -19.135 1.859 -24.817 1.00 0.00 <br />
ATOM 251 CG LYS A 34 -18.413 0.520 -24.789 1.00 0.00 <br />
ATOM 252 CD LYS A 34 -19.064 -0.505 -25.711 1.00 0.00 <br />
ATOM 253 CE LYS A 34 -20.442 -0.915 -25.197 1.00 0.00 <br />
ATOM 254 NZ LYS A 34 -21.063 -1.980 -26.035 1.00 0.00 <br />
ATOM 255 N LYS A 35 -20.638 2.228 -22.169 1.00 0.00 <br />
ATOM 256 CA LYS A 35 -21.311 1.609 -21.037 1.00 0.00 <br />
ATOM 257 C LYS A 35 -21.391 0.141 -21.441 1.00 0.00 <br />
ATOM 258 O LYS A 35 -21.684 -0.160 -22.597 1.00 0.00 <br />
ATOM 259 CB LYS A 35 -22.716 2.190 -20.873 1.00 0.00 <br />
ATOM 260 CG LYS A 35 -22.736 3.676 -20.514 1.00 0.00 <br />
ATOM 261 CD LYS A 35 -24.154 4.236 -20.479 1.00 0.00 <br />
ATOM 262 CE LYS A 35 -24.787 4.206 -21.868 1.00 0.00 <br />
ATOM 263 NZ LYS A 35 -26.128 4.854 -21.908 1.00 0.00 <br />
ATOM 264 N PHE A 36 -21.128 -0.769 -20.510 1.00 0.00 <br />
ATOM 265 CA PHE A 36 -21.158 -2.189 -20.842 1.00 0.00 <br />
ATOM 266 C PHE A 36 -22.232 -2.976 -20.104 1.00 0.00 <br />
ATOM 267 O PHE A 36 -22.508 -4.124 -20.445 1.00 0.00 <br />
ATOM 268 CB PHE A 36 -19.777 -2.815 -20.593 1.00 0.00 <br />
ATOM 269 CG PHE A 36 -19.232 -2.572 -19.209 1.00 0.00 <br />
ATOM 270 CD1 PHE A 36 -19.712 -3.287 -18.118 1.00 0.00 <br />
ATOM 271 CD2 PHE A 36 -18.236 -1.618 -18.999 1.00 0.00 <br />
ATOM 272 CE1 PHE A 36 -19.205 -3.056 -16.834 1.00 0.00 <br />
ATOM 273 CE2 PHE A 36 -17.726 -1.380 -17.724 1.00 0.00 <br />
ATOM 274 CZ PHE A 36 -18.213 -2.103 -16.640 1.00 0.00 <br />
ATOM 275 N ASP A 37 -22.847 -2.363 -19.099 1.00 0.00 <br />
ATOM 276 CA ASP A 37 -23.888 -3.052 -18.350 1.00 0.00 <br />
ATOM 277 C ASP A 37 -24.728 -2.064 -17.552 1.00 0.00 <br />
ATOM 278 O ASP A 37 -24.242 -1.013 -17.128 1.00 0.00 <br />
ATOM 279 CB ASP A 37 -23.264 -4.088 -17.408 1.00 0.00 <br />
ATOM 280 CG ASP A 37 -24.275 -5.107 -16.911 1.00 0.00 <br />
ATOM 281 OD1 ASP A 37 -25.448 -5.030 -17.330 1.00 0.00 <br />
ATOM 282 OD2 ASP A 37 -23.902 -5.987 -16.110 1.00 0.00 <br />
ATOM 283 N SER A 38 -25.997 -2.404 -17.358 1.00 0.00 <br />
ATOM 284 CA SER A 38 -26.901 -1.548 -16.603 1.00 0.00 <br />
ATOM 285 C SER A 38 -28.049 -2.351 -16.013 1.00 0.00 <br />
ATOM 286 O SER A 38 -28.886 -2.886 -16.743 1.00 0.00 <br />
ATOM 287 CB SER A 38 -27.462 -0.441 -17.503 1.00 0.00 <br />
ATOM 288 OG SER A 38 -28.493 0.280 -16.846 1.00 0.00 <br />
ATOM 289 N SER A 39 -28.078 -2.442 -14.687 1.00 0.00 <br />
ATOM 290 CA SER A 39 -29.145 -3.159 -14.003 1.00 0.00 <br />
ATOM 291 C SER A 39 -30.408 -2.309 -14.118 1.00 0.00 <br />
ATOM 292 O SER A 39 -31.523 -2.822 -14.055 1.00 0.00 <br />
ATOM 293 CB SER A 39 -28.796 -3.363 -12.525 1.00 0.00 <br />
ATOM 294 OG SER A 39 -28.735 -2.119 -11.842 1.00 0.00 <br />
ATOM 295 N ARG A 40 -30.220 -1.003 -14.289 1.00 0.00 <br />
ATOM 296 CA ARG A 40 -31.340 -0.074 -14.416 1.00 0.00 <br />
ATOM 297 C ARG A 40 -32.046 -0.233 -15.762 1.00 0.00 <br />
ATOM 298 O ARG A 40 -33.268 -0.120 -15.839 1.00 0.00 <br />
ATOM 299 CB ARG A 40 -30.860 1.376 -14.262 1.00 0.00 <br />
ATOM 300 CG ARG A 40 -30.171 1.692 -12.932 1.00 0.00 <br />
ATOM 301 CD ARG A 40 -29.980 3.199 -12.746 1.00 0.00 <br />
ATOM 302 NE ARG A 40 -29.299 3.527 -11.494 1.00 0.00 <br />
ATOM 303 CZ ARG A 40 -27.977 3.548 -11.339 1.00 0.00 <br />
ATOM 304 NH1 ARG A 40 -27.178 3.265 -12.361 1.00 0.00 <br />
ATOM 305 NH2 ARG A 40 -27.449 3.841 -10.153 1.00 0.00 <br />
ATOM 306 N ASP A 41 -31.276 -0.491 -16.818 1.00 0.00 <br />
ATOM 307 CA ASP A 41 -31.847 -0.660 -18.154 1.00 0.00 <br />
ATOM 308 C ASP A 41 -32.739 -1.890 -18.276 1.00 0.00 <br />
ATOM 309 O ASP A 41 -33.630 -1.937 -19.128 1.00 0.00 <br />
ATOM 310 CB ASP A 41 -30.746 -0.731 -19.217 1.00 0.00 <br />
ATOM 311 CG ASP A 41 -30.151 0.634 -19.535 1.00 0.00 <br />
ATOM 312 OD1 ASP A 41 -30.877 1.647 -19.413 1.00 0.00 <br />
ATOM 313 OD2 ASP A 41 -28.964 0.691 -19.925 1.00 0.00 <br />
ATOM 314 N ARG A 42 -32.489 -2.895 -17.444 1.00 0.00 <br />
ATOM 315 CA ARG A 42 -33.302 -4.107 -17.468 1.00 0.00 <br />
ATOM 316 C ARG A 42 -34.241 -4.125 -16.269 1.00 0.00 <br />
ATOM 317 O ARG A 42 -34.891 -5.134 -15.990 1.00 0.00 <br />
ATOM 318 CB ARG A 42 -32.417 -5.356 -17.459 1.00 0.00 <br />
ATOM 319 CG ARG A 42 -31.297 -5.319 -16.444 1.00 0.00 <br />
ATOM 320 CD ARG A 42 -30.666 -6.691 -16.265 1.00 0.00 <br />
ATOM 321 NE ARG A 42 -29.464 -6.621 -15.438 1.00 0.00 <br />
ATOM 322 CZ ARG A 42 -28.287 -6.179 -15.867 1.00 0.00 <br />
ATOM 323 NH1 ARG A 42 -28.146 -5.769 -17.122 1.00 0.00 <br />
ATOM 324 NH2 ARG A 42 -27.250 -6.139 -15.040 1.00 0.00 <br />
ATOM 325 N ASN A 43 -34.319 -2.988 -15.579 1.00 0.00 <br />
ATOM 326 CA ASN A 43 -35.175 -2.829 -14.406 1.00 0.00 <br />
ATOM 327 C ASN A 43 -35.087 -4.044 -13.488 1.00 0.00 <br />
ATOM 328 O ASN A 43 -36.086 -4.718 -13.240 1.00 0.00 <br />
ATOM 329 CB ASN A 43 -36.634 -2.621 -14.832 1.00 0.00 <br />
ATOM 330 CG ASN A 43 -36.826 -1.385 -15.700 1.00 0.00 <br />
ATOM 331 OD1 ASN A 43 -36.462 -1.371 -16.879 1.00 0.00 <br />
ATOM 332 ND2 ASN A 43 -37.400 -0.339 -15.115 1.00 0.00 <br />
ATOM 333 N LYS A 44 -33.893 -4.322 -12.982 1.00 0.00 <br />
ATOM 334 CA LYS A 44 -33.703 -5.468 -12.103 1.00 0.00 <br />
ATOM 335 C LYS A 44 -32.517 -5.268 -11.166 1.00 0.00 <br />
ATOM 336 O LYS A 44 -31.362 -5.377 -11.579 1.00 0.00 <br />
ATOM 337 CB LYS A 44 -33.500 -6.736 -12.942 1.00 0.00 <br />
ATOM 338 CG LYS A 44 -33.408 -8.027 -12.139 1.00 0.00 <br />
ATOM 339 CD LYS A 44 -33.426 -9.243 -13.063 1.00 0.00 <br />
ATOM 340 CE LYS A 44 -33.317 -10.554 -12.291 1.00 0.00 <br />
ATOM 341 NZ LYS A 44 -31.978 -10.744 -11.666 1.00 0.00 <br />
ATOM 342 N PRO A 45 -32.793 -4.960 -9.888 1.00 0.00 <br />
ATOM 343 CA PRO A 45 -31.738 -4.748 -8.893 1.00 0.00 <br />
ATOM 344 C PRO A 45 -30.772 -5.928 -8.838 1.00 0.00 <br />
ATOM 345 O PRO A 45 -31.162 -7.077 -9.061 1.00 0.00 <br />
ATOM 346 CB PRO A 45 -32.522 -4.579 -7.598 1.00 0.00 <br />
ATOM 347 CG PRO A 45 -33.763 -3.883 -8.066 1.00 0.00 <br />
ATOM 348 CD PRO A 45 -34.118 -4.669 -9.310 1.00 0.00 <br />
ATOM 349 N PHE A 46 -29.514 -5.626 -8.539 1.00 0.00 <br />
ATOM 350 CA PHE A 46 -28.450 -6.619 -8.448 1.00 0.00 <br />
ATOM 351 C PHE A 46 -28.140 -6.901 -6.973 1.00 0.00 <br />
ATOM 352 O PHE A 46 -28.031 -5.971 -6.170 1.00 0.00 <br />
ATOM 353 CB PHE A 46 -27.201 -6.068 -9.142 1.00 0.00 <br />
ATOM 354 CG PHE A 46 -26.012 -6.979 -9.083 1.00 0.00 <br />
ATOM 355 CD1 PHE A 46 -25.932 -8.098 -9.908 1.00 0.00 <br />
ATOM 356 CD2 PHE A 46 -24.952 -6.703 -8.220 1.00 0.00 <br />
ATOM 357 CE1 PHE A 46 -24.806 -8.931 -9.877 1.00 0.00 <br />
ATOM 358 CE2 PHE A 46 -23.823 -7.527 -8.179 1.00 0.00 <br />
ATOM 359 CZ PHE A 46 -23.747 -8.641 -9.008 1.00 0.00 <br />
ATOM 360 N LYS A 47 -27.997 -8.174 -6.618 1.00 0.00 <br />
ATOM 361 CA LYS A 47 -27.697 -8.540 -5.235 1.00 0.00 <br />
ATOM 362 C LYS A 47 -26.396 -9.325 -5.123 1.00 0.00 <br />
ATOM 363 O LYS A 47 -26.051 -10.107 -6.012 1.00 0.00 <br />
ATOM 364 CB LYS A 47 -28.832 -9.389 -4.641 1.00 0.00 <br />
ATOM 365 CG LYS A 47 -30.208 -8.726 -4.643 1.00 0.00 <br />
ATOM 366 CD LYS A 47 -31.244 -9.609 -3.937 1.00 0.00 <br />
ATOM 367 CE LYS A 47 -32.640 -9.011 -4.018 1.00 0.00 <br />
ATOM 368 NZ LYS A 47 -33.644 -9.817 -3.269 1.00 0.00 <br />
ATOM 369 N PHE A 48 -25.672 -9.108 -4.031 1.00 0.00 <br />
ATOM 370 CA PHE A 48 -24.429 -9.829 -3.781 1.00 0.00 <br />
ATOM 371 C PHE A 48 -24.117 -9.793 -2.295 1.00 0.00 <br />
ATOM 372 O PHE A 48 -24.493 -8.851 -1.596 1.00 0.00 <br />
ATOM 373 CB PHE A 48 -23.255 -9.237 -4.575 1.00 0.00 <br />
ATOM 374 CG PHE A 48 -22.809 -7.880 -4.098 1.00 0.00 <br />
ATOM 375 CD1 PHE A 48 -23.532 -6.738 -4.423 1.00 0.00 <br />
ATOM 376 CD2 PHE A 48 -21.653 -7.745 -3.334 1.00 0.00 <br />
ATOM 377 CE1 PHE A 48 -23.105 -5.470 -3.995 1.00 0.00 <br />
ATOM 378 CE2 PHE A 48 -21.218 -6.489 -2.900 1.00 0.00 <br />
ATOM 379 CZ PHE A 48 -21.947 -5.350 -3.233 1.00 0.00 <br />
ATOM 380 N ARG A 49 -23.429 -10.829 -1.825 1.00 0.00 <br />
ATOM 381 CA ARG A 49 -23.059 -10.968 -0.418 1.00 0.00 <br />
ATOM 382 C ARG A 49 -21.734 -10.287 -0.090 1.00 0.00 <br />
ATOM 383 O ARG A 49 -20.716 -10.525 -0.748 1.00 0.00 <br />
ATOM 384 CB ARG A 49 -22.951 -12.452 -0.058 1.00 0.00 <br />
ATOM 385 CG ARG A 49 -24.171 -13.286 -0.420 1.00 0.00 <br />
ATOM 386 CD ARG A 49 -23.766 -14.719 -0.764 1.00 0.00 <br />
ATOM 387 NE ARG A 49 -23.007 -15.364 0.306 1.00 0.00 <br />
ATOM 388 CZ ARG A 49 -22.374 -16.527 0.179 1.00 0.00 <br />
ATOM 389 NH1 ARG A 49 -22.404 -17.182 -0.975 1.00 0.00 <br />
ATOM 390 NH2 ARG A 49 -21.708 -17.040 1.206 1.00 0.00 <br />
ATOM 391 N ILE A 50 -21.755 -9.451 0.942 1.00 0.00 <br />
ATOM 392 CA ILE A 50 -20.566 -8.739 1.395 1.00 0.00 <br />
ATOM 393 C ILE A 50 -19.517 -9.697 1.954 1.00 0.00 <br />
ATOM 394 O ILE A 50 -19.832 -10.568 2.758 1.00 0.00 <br />
ATOM 395 CB ILE A 50 -20.925 -7.719 2.508 1.00 0.00 <br />
ATOM 396 CG1 ILE A 50 -21.499 -6.444 1.886 1.00 0.00 <br />
ATOM 397 CG2 ILE A 50 -19.697 -7.414 3.361 1.00 0.00 <br />
ATOM 398 CD1 ILE A 50 -20.498 -5.673 1.043 1.00 0.00 <br />
ATOM 399 N GLY A 51 -18.272 -9.530 1.522 1.00 0.00 <br />
ATOM 400 CA GLY A 51 -17.189 -10.361 2.021 1.00 0.00 <br />
ATOM 401 C GLY A 51 -17.100 -11.785 1.506 1.00 0.00 <br />
ATOM 402 O GLY A 51 -16.335 -12.591 2.044 1.00 0.00 <br />
ATOM 403 N LYS A 52 -17.870 -12.107 0.472 1.00 0.00 <br />
ATOM 404 CA LYS A 52 -17.849 -13.452 -0.086 1.00 0.00 <br />
ATOM 405 C LYS A 52 -17.088 -13.521 -1.405 1.00 0.00 <br />
ATOM 406 O LYS A 52 -17.124 -14.539 -2.097 1.00 0.00 <br />
ATOM 407 CB LYS A 52 -19.277 -13.965 -0.282 1.00 0.00 <br />
ATOM 408 CG LYS A 52 -20.037 -14.182 1.018 1.00 0.00 <br />
ATOM 409 CD LYS A 52 -19.334 -15.209 1.898 1.00 0.00 <br />
ATOM 410 CE LYS A 52 -20.107 -15.474 3.179 1.00 0.00 <br />
ATOM 411 NZ LYS A 52 -19.443 -16.511 4.020 1.00 0.00 <br />
ATOM 412 N GLN A 53 -16.403 -12.435 -1.749 1.00 0.00 <br />
ATOM 413 CA GLN A 53 -15.627 -12.380 -2.984 1.00 0.00 <br />
ATOM 414 C GLN A 53 -16.453 -12.745 -4.212 1.00 0.00 <br />
ATOM 415 O GLN A 53 -15.972 -13.447 -5.103 1.00 0.00 <br />
ATOM 416 CB GLN A 53 -14.432 -13.326 -2.889 1.00 0.00 <br />
ATOM 417 CG GLN A 53 -13.499 -13.013 -1.738 1.00 0.00 <br />
ATOM 418 CD GLN A 53 -12.503 -14.119 -1.491 1.00 0.00 <br />
ATOM 419 OE1 GLN A 53 -12.881 -15.255 -1.200 1.00 0.00 <br />
ATOM 420 NE2 GLN A 53 -11.219 -13.796 -1.602 1.00 0.00 <br />
ATOM 421 N GLU A 54 -17.692 -12.271 -4.268 1.00 0.00 <br />
ATOM 422 CA GLU A 54 -18.543 -12.569 -5.416 1.00 0.00 <br />
ATOM 423 C GLU A 54 -18.362 -11.547 -6.533 1.00 0.00 <br />
ATOM 424 O GLU A 54 -18.608 -11.846 -7.702 1.00 0.00 <br />
ATOM 425 CB GLU A 54 -20.012 -12.595 -4.999 1.00 0.00 <br />
ATOM 426 CG GLU A 54 -20.307 -13.506 -3.826 1.00 0.00 <br />
ATOM 427 CD GLU A 54 -21.785 -13.651 -3.582 1.00 0.00 <br />
ATOM 428 OE1 GLU A 54 -22.499 -12.628 -3.654 1.00 0.00 <br />
ATOM 429 OE2 GLU A 54 -22.232 -14.786 -3.313 1.00 0.00 <br />
ATOM 430 N VAL A 55 -17.933 -10.341 -6.172 1.00 0.00 <br />
ATOM 431 CA VAL A 55 -17.741 -9.276 -7.152 1.00 0.00 <br />
ATOM 432 C VAL A 55 -16.340 -8.677 -7.046 1.00 0.00 <br />
ATOM 433 O VAL A 55 -15.673 -8.827 -6.022 1.00 0.00 <br />
ATOM 434 CB VAL A 55 -18.788 -8.160 -6.951 1.00 0.00 <br />
ATOM 435 CG1 VAL A 55 -20.200 -8.755 -7.006 1.00 0.00 <br />
ATOM 436 CG2 VAL A 55 -18.560 -7.464 -5.613 1.00 0.00 <br />
ATOM 437 N ILE A 56 -15.894 -7.999 -8.100 1.00 0.00 <br />
ATOM 438 CA ILE A 56 -14.564 -7.394 -8.092 1.00 0.00 <br />
ATOM 439 C ILE A 56 -14.374 -6.523 -6.853 1.00 0.00 <br />
ATOM 440 O ILE A 56 -15.321 -5.901 -6.371 1.00 0.00 <br />
ATOM 441 CB ILE A 56 -14.307 -6.554 -9.375 1.00 0.00 <br />
ATOM 442 CG1 ILE A 56 -15.440 -5.551 -9.602 1.00 0.00 <br />
ATOM 443 CG2 ILE A 56 -14.182 -7.488 -10.575 1.00 0.00 <br />
ATOM 444 CD1 ILE A 56 -15.210 -4.630 -10.793 1.00 0.00 <br />
ATOM 445 N LYS A 57 -13.144 -6.485 -6.345 1.00 0.00 <br />
ATOM 446 CA LYS A 57 -12.824 -5.723 -5.138 1.00 0.00 <br />
ATOM 447 C LYS A 57 -13.315 -4.287 -5.109 1.00 0.00 <br />
ATOM 448 O LYS A 57 -13.879 -3.841 -4.111 1.00 0.00 <br />
ATOM 449 CB LYS A 57 -11.313 -5.731 -4.885 1.00 0.00 <br />
ATOM 450 CG LYS A 57 -10.787 -7.039 -4.334 1.00 0.00 <br />
ATOM 451 CD LYS A 57 -9.324 -6.910 -3.923 1.00 0.00 <br />
ATOM 452 CE LYS A 57 -8.825 -8.180 -3.246 1.00 0.00 <br />
ATOM 453 NZ LYS A 57 -7.395 -8.065 -2.826 1.00 0.00 <br />
ATOM 454 N GLY A 58 -13.080 -3.562 -6.199 1.00 0.00 <br />
ATOM 455 CA GLY A 58 -13.492 -2.175 -6.264 1.00 0.00 <br />
ATOM 456 C GLY A 58 -14.979 -1.931 -6.085 1.00 0.00 <br />
ATOM 457 O GLY A 58 -15.385 -0.942 -5.471 1.00 0.00 <br />
ATOM 458 N PHE A 59 -15.797 -2.826 -6.624 1.00 0.00 <br />
ATOM 459 CA PHE A 59 -17.242 -2.687 -6.527 1.00 0.00 <br />
ATOM 460 C PHE A 59 -17.673 -2.948 -5.086 1.00 0.00 <br />
ATOM 461 O PHE A 59 -18.462 -2.191 -4.519 1.00 0.00 <br />
ATOM 462 CB PHE A 59 -17.915 -3.664 -7.498 1.00 0.00 <br />
ATOM 463 CG PHE A 59 -19.390 -3.413 -7.703 1.00 0.00 <br />
ATOM 464 CD1 PHE A 59 -20.328 -3.891 -6.788 1.00 0.00 <br />
ATOM 465 CD2 PHE A 59 -19.840 -2.725 -8.828 1.00 0.00 <br />
ATOM 466 CE1 PHE A 59 -21.693 -3.692 -6.990 1.00 0.00 <br />
ATOM 467 CE2 PHE A 59 -21.204 -2.517 -9.044 1.00 0.00 <br />
ATOM 468 CZ PHE A 59 -22.136 -3.003 -8.123 1.00 0.00 <br />
ATOM 469 N GLU A 60 -17.132 -4.001 -4.482 1.00 0.00 <br />
ATOM 470 CA GLU A 60 -17.483 -4.323 -3.105 1.00 0.00 <br />
ATOM 471 C GLU A 60 -16.952 -3.283 -2.119 1.00 0.00 <br />
ATOM 472 O GLU A 60 -17.652 -2.894 -1.191 1.00 0.00 <br />
ATOM 473 CB GLU A 60 -16.958 -5.706 -2.707 1.00 0.00 <br />
ATOM 474 CG GLU A 60 -17.614 -6.211 -1.425 1.00 0.00 <br />
ATOM 475 CD GLU A 60 -17.145 -7.584 -1.006 1.00 0.00 <br />
ATOM 476 OE1 GLU A 60 -16.906 -8.432 -1.892 1.00 0.00 <br />
ATOM 477 OE2 GLU A 60 -17.035 -7.820 0.218 1.00 0.00 <br />
ATOM 478 N GLU A 61 -15.713 -2.837 -2.311 1.00 0.00 <br />
ATOM 479 CA GLU A 61 -15.147 -1.839 -1.410 1.00 0.00 <br />
ATOM 480 C GLU A 61 -15.923 -0.531 -1.516 1.00 0.00 <br />
ATOM 481 O GLU A 61 -16.061 0.204 -0.537 1.00 0.00 <br />
ATOM 482 CB GLU A 61 -13.669 -1.603 -1.728 1.00 0.00 <br />
ATOM 483 CG GLU A 61 -12.814 -2.848 -1.570 1.00 0.00 <br />
ATOM 484 CD GLU A 61 -11.345 -2.583 -1.813 1.00 0.00 <br />
ATOM 485 OE1 GLU A 61 -11.027 -1.644 -2.575 1.00 0.00 <br />
ATOM 486 OE2 GLU A 61 -10.510 -3.324 -1.255 1.00 0.00 <br />
ATOM 487 N GLY A 62 -16.429 -0.240 -2.709 1.00 0.00 <br />
ATOM 488 CA GLY A 62 -17.199 0.974 -2.888 1.00 0.00 <br />
ATOM 489 C GLY A 62 -18.501 0.877 -2.109 1.00 0.00 <br />
ATOM 490 O GLY A 62 -18.852 1.769 -1.333 1.00 0.00 <br />
ATOM 491 N ALA A 63 -19.212 -0.228 -2.306 1.00 0.00 <br />
ATOM 492 CA ALA A 63 -20.487 -0.447 -1.635 1.00 0.00 <br />
ATOM 493 C ALA A 63 -20.334 -0.496 -0.123 1.00 0.00 <br />
ATOM 494 O ALA A 63 -21.180 0.016 0.615 1.00 0.00 <br />
ATOM 495 CB ALA A 63 -21.115 -1.742 -2.131 1.00 0.00 <br />
ATOM 496 N ALA A 64 -19.252 -1.118 0.337 1.00 0.00 <br />
ATOM 497 CA ALA A 64 -19.001 -1.252 1.764 1.00 0.00 <br />
ATOM 498 C ALA A 64 -18.902 0.092 2.481 1.00 0.00 <br />
ATOM 499 O ALA A 64 -19.242 0.190 3.661 1.00 0.00 <br />
ATOM 500 CB ALA A 64 -17.731 -2.069 1.996 1.00 0.00 <br />
ATOM 501 N GLN A 65 -18.452 1.129 1.779 1.00 0.00 <br />
ATOM 502 CA GLN A 65 -18.321 2.444 2.408 1.00 0.00 <br />
ATOM 503 C GLN A 65 -19.489 3.386 2.132 1.00 0.00 <br />
ATOM 504 O GLN A 65 -19.404 4.588 2.396 1.00 0.00 <br />
ATOM 505 CB GLN A 65 -17.011 3.111 1.981 1.00 0.00 <br />
ATOM 506 CG GLN A 65 -16.896 3.386 0.498 1.00 0.00 <br />
ATOM 507 CD GLN A 65 -15.542 3.956 0.135 1.00 0.00 <br />
ATOM 508 OE1 GLN A 65 -15.246 5.122 0.416 1.00 0.00 <br />
ATOM 509 NE2 GLN A 65 -14.705 3.135 -0.473 1.00 0.00 <br />
ATOM 510 N MET A 66 -20.574 2.837 1.599 1.00 0.00 <br />
ATOM 511 CA MET A 66 -21.769 3.621 1.297 1.00 0.00 <br />
ATOM 512 C MET A 66 -22.858 3.312 2.322 1.00 0.00 <br />
ATOM 513 O MET A 66 -22.951 2.186 2.809 1.00 0.00 <br />
ATOM 514 CB MET A 66 -22.278 3.286 -0.107 1.00 0.00 <br />
ATOM 515 CG MET A 66 -21.360 3.779 -1.227 1.00 0.00 <br />
ATOM 516 SD MET A 66 -21.802 3.102 -2.840 1.00 0.00 <br />
ATOM 517 CE MET A 66 -23.385 3.919 -3.121 1.00 0.00 <br />
ATOM 518 N SER A 67 -23.673 4.307 2.655 1.00 0.00 <br />
ATOM 519 CA SER A 67 -24.753 4.094 3.613 1.00 0.00 <br />
ATOM 520 C SER A 67 -26.065 3.852 2.864 1.00 0.00 <br />
ATOM 521 O SER A 67 -26.175 4.150 1.668 1.00 0.00 <br />
ATOM 522 CB SER A 67 -24.879 5.289 4.574 1.00 0.00 <br />
ATOM 523 OG SER A 67 -25.060 6.519 3.893 1.00 0.00 <br />
ATOM 524 N LEU A 68 -27.052 3.300 3.565 1.00 0.00 <br />
ATOM 525 CA LEU A 68 -28.343 2.990 2.959 1.00 0.00 <br />
ATOM 526 C LEU A 68 -28.934 4.161 2.183 1.00 0.00 <br />
ATOM 527 O LEU A 68 -29.022 5.274 2.697 1.00 0.00 <br />
ATOM 528 CB LEU A 68 -29.337 2.534 4.033 1.00 0.00 <br />
ATOM 529 CG LEU A 68 -30.677 2.004 3.514 1.00 0.00 <br />
ATOM 530 CD1 LEU A 68 -30.438 0.840 2.560 1.00 0.00 <br />
ATOM 531 CD2 LEU A 68 -31.539 1.556 4.689 1.00 0.00 <br />
ATOM 532 N GLY A 69 -29.331 3.896 0.940 1.00 0.00 <br />
ATOM 533 CA GLY A 69 -29.915 4.928 0.094 1.00 0.00 <br />
ATOM 534 C GLY A 69 -28.910 5.768 -0.678 1.00 0.00 <br />
ATOM 535 O GLY A 69 -29.282 6.535 -1.569 1.00 0.00 <br />
ATOM 536 N GLN A 70 -27.629 5.632 -0.348 1.00 0.00 <br />
ATOM 537 CA GLN A 70 -26.611 6.413 -1.033 1.00 0.00 <br />
ATOM 538 C GLN A 70 -26.414 5.947 -2.464 1.00 0.00 <br />
ATOM 539 O GLN A 70 -26.568 4.764 -2.770 1.00 0.00 <br />
ATOM 540 CB GLN A 70 -25.268 6.322 -0.299 1.00 0.00 <br />
ATOM 541 CG GLN A 70 -24.212 7.269 -0.843 1.00 0.00 <br />
ATOM 542 CD GLN A 70 -22.892 7.173 -0.083 1.00 0.00 <br />
ATOM 543 OE1 GLN A 70 -22.825 6.580 0.993 1.00 0.00 <br />
ATOM 544 NE2 GLN A 70 -21.841 7.771 -0.640 1.00 0.00 <br />
ATOM 545 N ARG A 71 -26.081 6.899 -3.334 1.00 0.00 <br />
ATOM 546 CA ARG A 71 -25.802 6.632 -4.739 1.00 0.00 <br />
ATOM 547 C ARG A 71 -24.497 7.348 -5.030 1.00 0.00 <br />
ATOM 548 O ARG A 71 -24.319 8.513 -4.659 1.00 0.00 <br />
ATOM 549 CB ARG A 71 -26.902 7.190 -5.646 1.00 0.00 <br />
ATOM 550 CG ARG A 71 -26.590 7.038 -7.127 1.00 0.00 <br />
ATOM 551 CD ARG A 71 -27.729 7.569 -7.984 1.00 0.00 <br />
ATOM 552 NE ARG A 71 -27.481 7.406 -9.413 1.00 0.00 <br />
ATOM 553 CZ ARG A 71 -28.266 7.914 -10.361 1.00 0.00 <br />
ATOM 554 NH1 ARG A 71 -29.343 8.617 -10.021 1.00 0.00 <br />
ATOM 555 NH2 ARG A 71 -27.983 7.719 -11.644 1.00 0.00 <br />
ATOM 556 N ALA A 72 -23.575 6.664 -5.692 1.00 0.00 <br />
ATOM 557 CA ALA A 72 -22.300 7.284 -5.968 1.00 0.00 <br />
ATOM 558 C ALA A 72 -21.643 6.762 -7.226 1.00 0.00 <br />
ATOM 559 O ALA A 72 -21.975 5.689 -7.726 1.00 0.00 <br />
ATOM 560 CB ALA A 72 -21.367 7.083 -4.781 1.00 0.00 <br />
ATOM 561 N LYS A 73 -20.706 7.552 -7.728 1.00 0.00 <br />
ATOM 562 CA LYS A 73 -19.935 7.202 -8.907 1.00 0.00 <br />
ATOM 563 C LYS A 73 -18.658 6.549 -8.385 1.00 0.00 <br />
ATOM 564 O LYS A 73 -17.917 7.162 -7.608 1.00 0.00 <br />
ATOM 565 CB LYS A 73 -19.588 8.471 -9.689 1.00 0.00 <br />
ATOM 566 CG LYS A 73 -18.573 8.289 -10.805 1.00 0.00 <br />
ATOM 567 CD LYS A 73 -18.169 9.649 -11.368 1.00 0.00 <br />
ATOM 568 CE LYS A 73 -17.260 9.522 -12.575 1.00 0.00 <br />
ATOM 569 NZ LYS A 73 -16.030 8.757 -12.253 1.00 0.00 <br />
ATOM 570 N LEU A 74 -18.405 5.303 -8.780 1.00 0.00 <br />
ATOM 571 CA LEU A 74 -17.196 4.628 -8.326 1.00 0.00 <br />
ATOM 572 C LEU A 74 -16.200 4.546 -9.470 1.00 0.00 <br />
ATOM 573 O LEU A 74 -16.546 4.130 -10.578 1.00 0.00 <br />
ATOM 574 CB LEU A 74 -17.487 3.201 -7.844 1.00 0.00 <br />
ATOM 575 CG LEU A 74 -18.759 2.834 -7.078 1.00 0.00 <br />
ATOM 576 CD1 LEU A 74 -18.576 1.442 -6.495 1.00 0.00 <br />
ATOM 577 CD2 LEU A 74 -19.045 3.828 -5.981 1.00 0.00 <br />
ATOM 578 N THR A 75 -14.967 4.958 -9.209 1.00 0.00 <br />
ATOM 579 CA THR A 75 -13.935 4.865 -10.222 1.00 0.00 <br />
ATOM 580 C THR A 75 -12.982 3.799 -9.704 1.00 0.00 <br />
ATOM 581 O THR A 75 -12.352 3.969 -8.658 1.00 0.00 <br />
ATOM 582 CB THR A 75 -13.196 6.197 -10.409 1.00 0.00 <br />
ATOM 583 OG1 THR A 75 -14.144 7.221 -10.746 1.00 0.00 <br />
ATOM 584 CG2 THR A 75 -12.171 6.078 -11.536 1.00 0.00 <br />
ATOM 585 N CYS A 76 -12.897 2.695 -10.437 1.00 0.00 <br />
ATOM 586 CA CYS A 76 -12.063 1.569 -10.044 1.00 0.00 <br />
ATOM 587 C CYS A 76 -10.873 1.349 -10.972 1.00 0.00 <br />
ATOM 588 O CYS A 76 -11.045 1.139 -12.174 1.00 0.00 <br />
ATOM 589 CB CYS A 76 -12.909 0.292 -10.016 1.00 0.00 <br />
ATOM 590 SG CYS A 76 -14.468 0.417 -9.079 1.00 0.00 <br />
ATOM 591 N THR A 77 -9.669 1.395 -10.411 1.00 0.00 <br />
ATOM 592 CA THR A 77 -8.467 1.159 -11.203 1.00 0.00 <br />
ATOM 593 C THR A 77 -8.425 -0.340 -11.518 1.00 0.00 <br />
ATOM 594 O THR A 77 -9.075 -1.147 -10.845 1.00 0.00 <br />
ATOM 595 CB THR A 77 -7.188 1.575 -10.434 1.00 0.00 <br />
ATOM 596 OG1 THR A 77 -7.215 1.014 -9.116 1.00 0.00 <br />
ATOM 597 CG2 THR A 77 -7.096 3.094 -10.336 1.00 0.00 <br />
ATOM 598 N PRO A 78 -7.664 -0.731 -12.551 1.00 0.00 <br />
ATOM 599 CA PRO A 78 -7.550 -2.137 -12.953 1.00 0.00 <br />
ATOM 600 C PRO A 78 -7.252 -3.129 -11.823 1.00 0.00 <br />
ATOM 601 O PRO A 78 -7.852 -4.205 -11.765 1.00 0.00 <br />
ATOM 602 CB PRO A 78 -6.432 -2.110 -13.995 1.00 0.00 <br />
ATOM 603 CG PRO A 78 -6.552 -0.742 -14.588 1.00 0.00 <br />
ATOM 604 CD PRO A 78 -6.785 0.122 -13.373 1.00 0.00 <br />
ATOM 605 N ASP A 79 -6.335 -2.771 -10.926 1.00 0.00 <br />
ATOM 606 CA ASP A 79 -5.965 -3.672 -9.836 1.00 0.00 <br />
ATOM 607 C ASP A 79 -7.124 -4.062 -8.914 1.00 0.00 <br />
ATOM 608 O ASP A 79 -7.050 -5.081 -8.227 1.00 0.00 <br />
ATOM 609 CB ASP A 79 -4.814 -3.077 -9.015 1.00 0.00 <br />
ATOM 610 CG ASP A 79 -5.149 -1.726 -8.445 1.00 0.00 <br />
ATOM 611 OD1 ASP A 79 -5.459 -0.813 -9.233 1.00 0.00 <br />
ATOM 612 OD2 ASP A 79 -5.101 -1.574 -7.212 1.00 0.00 <br />
ATOM 613 N VAL A 80 -8.183 -3.254 -8.885 1.00 0.00 <br />
ATOM 614 CA VAL A 80 -9.349 -3.580 -8.067 1.00 0.00 <br />
ATOM 615 C VAL A 80 -10.546 -3.901 -8.971 1.00 0.00 <br />
ATOM 616 O VAL A 80 -11.698 -3.845 -8.544 1.00 0.00 <br />
ATOM 617 CB VAL A 80 -9.716 -2.432 -7.082 1.00 0.00 <br />
ATOM 618 CG1 VAL A 80 -8.655 -2.336 -5.979 1.00 0.00 <br />
ATOM 619 CG2 VAL A 80 -9.832 -1.108 -7.826 1.00 0.00 <br />
ATOM 620 N ALA A 81 -10.252 -4.235 -10.227 1.00 0.00 <br />
ATOM 621 CA ALA A 81 -11.277 -4.602 -11.196 1.00 0.00 <br />
ATOM 622 C ALA A 81 -10.854 -5.906 -11.884 1.00 0.00 <br />
ATOM 623 O ALA A 81 -10.777 -6.951 -11.233 1.00 0.00 <br />
ATOM 624 CB ALA A 81 -11.466 -3.486 -12.227 1.00 0.00 <br />
ATOM 625 N TYR A 82 -10.555 -5.848 -13.180 1.00 0.00 <br />
ATOM 626 CA TYR A 82 -10.157 -7.049 -13.914 1.00 0.00 <br />
ATOM 627 C TYR A 82 -8.664 -7.146 -14.248 1.00 0.00 <br />
ATOM 628 O TYR A 82 -8.232 -8.062 -14.952 1.00 0.00 <br />
ATOM 629 CB TYR A 82 -11.020 -7.178 -15.178 1.00 0.00 <br />
ATOM 630 CG TYR A 82 -12.484 -7.397 -14.844 1.00 0.00 <br />
ATOM 631 CD1 TYR A 82 -12.947 -8.650 -14.432 1.00 0.00 <br />
ATOM 632 CD2 TYR A 82 -13.393 -6.338 -14.870 1.00 0.00 <br />
ATOM 633 CE1 TYR A 82 -14.280 -8.841 -14.046 1.00 0.00 <br />
ATOM 634 CE2 TYR A 82 -14.730 -6.518 -14.490 1.00 0.00 <br />
ATOM 635 CZ TYR A 82 -15.162 -7.770 -14.076 1.00 0.00 <br />
ATOM 636 OH TYR A 82 -16.466 -7.938 -13.668 1.00 0.00 <br />
ATOM 637 N GLY A 83 -7.885 -6.198 -13.739 1.00 0.00 <br />
ATOM 638 CA GLY A 83 -6.445 -6.208 -13.944 1.00 0.00 <br />
ATOM 639 C GLY A 83 -5.895 -6.301 -15.357 1.00 0.00 <br />
ATOM 640 O GLY A 83 -6.486 -5.792 -16.307 1.00 0.00 <br />
ATOM 641 N ALA A 84 -4.746 -6.959 -15.486 1.00 0.00 <br />
ATOM 642 CA ALA A 84 -4.080 -7.109 -16.776 1.00 0.00 <br />
ATOM 643 C ALA A 84 -4.792 -8.114 -17.665 1.00 0.00 <br />
ATOM 644 O ALA A 84 -4.618 -8.108 -18.883 1.00 0.00 <br />
ATOM 645 CB ALA A 84 -2.636 -7.538 -16.568 1.00 0.00 <br />
ATOM 646 N THR A 85 -5.596 -8.971 -17.048 1.00 0.00 <br />
ATOM 647 CA THR A 85 -6.330 -9.998 -17.776 1.00 0.00 <br />
ATOM 648 C THR A 85 -7.594 -9.470 -18.440 1.00 0.00 <br />
ATOM 649 O THR A 85 -7.944 -9.903 -19.538 1.00 0.00 <br />
ATOM 650 CB THR A 85 -6.745 -11.156 -16.843 1.00 0.00 <br />
ATOM 651 OG1 THR A 85 -5.584 -11.705 -16.214 1.00 0.00 <br />
ATOM 652 CG2 THR A 85 -7.459 -12.252 -17.633 1.00 0.00 <br />
ATOM 653 N GLY A 86 -8.275 -8.542 -17.771 1.00 0.00 <br />
ATOM 654 CA GLY A 86 -9.514 -8.003 -18.301 1.00 0.00 <br />
ATOM 655 C GLY A 86 -10.593 -9.071 -18.186 1.00 0.00 <br />
ATOM 656 O GLY A 86 -10.348 -10.127 -17.610 1.00 0.00 <br />
ATOM 657 N HIS A 87 -11.787 -8.796 -18.704 1.00 0.00 <br />
ATOM 658 CA HIS A 87 -12.871 -9.776 -18.677 1.00 0.00 <br />
ATOM 659 C HIS A 87 -13.148 -10.182 -20.125 1.00 0.00 <br />
ATOM 660 O HIS A 87 -13.560 -9.354 -20.939 1.00 0.00 <br />
ATOM 661 CB HIS A 87 -14.139 -9.181 -18.057 1.00 0.00 <br />
ATOM 662 CG HIS A 87 -15.283 -10.143 -18.001 1.00 0.00 <br />
ATOM 663 ND1 HIS A 87 -15.322 -11.202 -17.118 1.00 0.00 <br />
ATOM 664 CD2 HIS A 87 -16.407 -10.233 -18.748 1.00 0.00 <br />
ATOM 665 CE1 HIS A 87 -16.424 -11.903 -17.324 1.00 0.00 <br />
ATOM 666 NE2 HIS A 87 -17.100 -11.337 -18.309 1.00 0.00 <br />
ATOM 667 N PRO A 88 -12.927 -11.464 -20.460 1.00 0.00 <br />
ATOM 668 CA PRO A 88 -13.140 -11.985 -21.813 1.00 0.00 <br />
ATOM 669 C PRO A 88 -14.260 -11.359 -22.632 1.00 0.00 <br />
ATOM 670 O PRO A 88 -15.435 -11.455 -22.277 1.00 0.00 <br />
ATOM 671 CB PRO A 88 -13.354 -13.476 -21.570 1.00 0.00 <br />
ATOM 672 CG PRO A 88 -12.350 -13.741 -20.477 1.00 0.00 <br />
ATOM 673 CD PRO A 88 -12.577 -12.558 -19.532 1.00 0.00 <br />
ATOM 674 N GLY A 89 -13.870 -10.708 -23.726 1.00 0.00 <br />
ATOM 675 CA GLY A 89 -14.820 -10.091 -24.638 1.00 0.00 <br />
ATOM 676 C GLY A 89 -15.633 -8.892 -24.181 1.00 0.00 <br />
ATOM 677 O GLY A 89 -16.491 -8.427 -24.926 1.00 0.00 <br />
ATOM 678 N VAL A 90 -15.378 -8.376 -22.982 1.00 0.00 <br />
ATOM 679 CA VAL A 90 -16.140 -7.228 -22.492 1.00 0.00 <br />
ATOM 680 C VAL A 90 -15.254 -6.116 -21.923 1.00 0.00 <br />
ATOM 681 O VAL A 90 -15.404 -4.945 -22.280 1.00 0.00 <br />
ATOM 682 CB VAL A 90 -17.147 -7.655 -21.395 1.00 0.00 <br />
ATOM 683 CG1 VAL A 90 -18.042 -6.484 -21.030 1.00 0.00 <br />
ATOM 684 CG2 VAL A 90 -17.979 -8.835 -21.881 1.00 0.00 <br />
ATOM 685 N ILE A 91 -14.338 -6.491 -21.034 1.00 0.00 <br />
ATOM 686 CA ILE A 91 -13.427 -5.533 -20.408 1.00 0.00 <br />
ATOM 687 C ILE A 91 -11.994 -5.844 -20.841 1.00 0.00 <br />
ATOM 688 O ILE A 91 -11.483 -6.937 -20.583 1.00 0.00 <br />
ATOM 689 CB ILE A 91 -13.467 -5.634 -18.864 1.00 0.00 <br />
ATOM 690 CG1 ILE A 91 -14.913 -5.540 -18.355 1.00 0.00 <br />
ATOM 691 CG2 ILE A 91 -12.562 -4.552 -18.250 1.00 0.00 <br />
ATOM 692 CD1 ILE A 91 -15.621 -4.225 -18.679 1.00 0.00 <br />
ATOM 693 N PRO A 92 -11.321 -4.886 -21.501 1.00 0.00 <br />
ATOM 694 CA PRO A 92 -9.941 -5.129 -21.936 1.00 0.00 <br />
ATOM 695 C PRO A 92 -8.929 -5.029 -20.802 1.00 0.00 <br />
ATOM 696 O PRO A 92 -9.249 -4.561 -19.706 1.00 0.00 <br />
ATOM 697 CB PRO A 92 -9.716 -4.042 -22.985 1.00 0.00 <br />
ATOM 698 CG PRO A 92 -10.539 -2.910 -22.458 1.00 0.00 <br />
ATOM 699 CD PRO A 92 -11.822 -3.607 -22.031 1.00 0.00 <br />
ATOM 700 N PRO A 93 -7.691 -5.487 -21.050 1.00 0.00 <br />
ATOM 701 CA PRO A 93 -6.636 -5.431 -20.038 1.00 0.00 <br />
ATOM 702 C PRO A 93 -6.411 -3.987 -19.571 1.00 0.00 <br />
ATOM 703 O PRO A 93 -6.597 -3.040 -20.345 1.00 0.00 <br />
ATOM 704 CB PRO A 93 -5.426 -5.984 -20.780 1.00 0.00 <br />
ATOM 705 CG PRO A 93 -6.045 -7.000 -21.701 1.00 0.00 <br />
ATOM 706 CD PRO A 93 -7.251 -6.261 -22.228 1.00 0.00 <br />
ATOM 707 N ASN A 94 -6.030 -3.837 -18.304 1.00 0.00 <br />
ATOM 708 CA ASN A 94 -5.740 -2.536 -17.692 1.00 0.00 <br />
ATOM 709 C ASN A 94 -6.852 -1.503 -17.804 1.00 0.00 <br />
ATOM 710 O ASN A 94 -6.586 -0.313 -17.988 1.00 0.00 <br />
ATOM 711 CB ASN A 94 -4.470 -1.934 -18.295 1.00 0.00 <br />
ATOM 712 CG ASN A 94 -3.777 -0.985 -17.335 1.00 0.00 <br />
ATOM 713 OD1 ASN A 94 -3.383 -1.387 -16.244 1.00 0.00 <br />
ATOM 714 ND2 ASN A 94 -3.630 0.271 -17.730 1.00 0.00 <br />
ATOM 715 N ALA A 95 -8.093 -1.941 -17.669 1.00 0.00 <br />
ATOM 716 CA ALA A 95 -9.198 -1.012 -17.786 1.00 0.00 <br />
ATOM 717 C ALA A 95 -9.671 -0.422 -16.469 1.00 0.00 <br />
ATOM 718 O ALA A 95 -9.956 -1.148 -15.512 1.00 0.00 <br />
ATOM 719 CB ALA A 95 -10.369 -1.684 -18.494 1.00 0.00 <br />
ATOM 720 N THR A 96 -9.736 0.904 -16.423 1.00 0.00 <br />
ATOM 721 CA THR A 96 -10.260 1.593 -15.252 1.00 0.00 <br />
ATOM 722 C THR A 96 -11.769 1.614 -15.502 1.00 0.00 <br />
ATOM 723 O THR A 96 -12.228 1.995 -16.589 1.00 0.00 <br />
ATOM 724 CB THR A 96 -9.700 3.031 -15.148 1.00 0.00 <br />
ATOM 725 OG1 THR A 96 -8.320 2.970 -14.751 1.00 0.00 <br />
ATOM 726 CG2 THR A 96 -10.492 3.849 -14.140 1.00 0.00 <br />
ATOM 727 N LEU A 97 -12.543 1.190 -14.510 1.00 0.00 <br />
ATOM 728 CA LEU A 97 -13.992 1.121 -14.674 1.00 0.00 <br />
ATOM 729 C LEU A 97 -14.761 2.144 -13.861 1.00 0.00 <br />
ATOM 730 O LEU A 97 -14.368 2.492 -12.747 1.00 0.00 <br />
ATOM 731 CB LEU A 97 -14.474 -0.283 -14.303 1.00 0.00 <br />
ATOM 732 CG LEU A 97 -13.732 -1.432 -14.998 1.00 0.00 <br />
ATOM 733 CD1 LEU A 97 -14.256 -2.769 -14.495 1.00 0.00 <br />
ATOM 734 CD2 LEU A 97 -13.910 -1.313 -16.508 1.00 0.00 <br />
ATOM 735 N ILE A 98 -15.865 2.618 -14.428 1.00 0.00 <br />
ATOM 736 CA ILE A 98 -16.720 3.582 -13.753 1.00 0.00 <br />
ATOM 737 C ILE A 98 -18.046 2.901 -13.478 1.00 0.00 <br />
ATOM 738 O ILE A 98 -18.666 2.370 -14.400 1.00 0.00 <br />
ATOM 739 CB ILE A 98 -17.013 4.822 -14.628 1.00 0.00 <br />
ATOM 740 CG1 ILE A 98 -15.711 5.516 -15.032 1.00 0.00 <br />
ATOM 741 CG2 ILE A 98 -17.929 5.777 -13.861 1.00 0.00 <br />
ATOM 742 CD1 ILE A 98 -14.936 6.099 -13.871 1.00 0.00 <br />
ATOM 743 N PHE A 99 -18.476 2.921 -12.217 1.00 0.00 <br />
ATOM 744 CA PHE A 99 -19.741 2.310 -11.814 1.00 0.00 <br />
ATOM 745 C PHE A 99 -20.619 3.308 -11.065 1.00 0.00 <br />
ATOM 746 O PHE A 99 -20.193 3.871 -10.056 1.00 0.00 <br />
ATOM 747 CB PHE A 99 -19.500 1.114 -10.882 1.00 0.00 <br />
ATOM 748 CG PHE A 99 -19.076 -0.153 -11.583 1.00 0.00 <br />
ATOM 749 CD1 PHE A 99 -20.014 -0.953 -12.233 1.00 0.00 <br />
ATOM 750 CD2 PHE A 99 -17.749 -0.566 -11.554 1.00 0.00 <br />
ATOM 751 CE1 PHE A 99 -19.630 -2.152 -12.841 1.00 0.00 <br />
ATOM 752 CE2 PHE A 99 -17.354 -1.757 -12.157 1.00 0.00 <br />
ATOM 753 CZ PHE A 99 -18.295 -2.554 -12.801 1.00 0.00 <br />
ATOM 754 N ASP A 100 -21.832 3.531 -11.567 1.00 0.00 <br />
ATOM 755 CA ASP A 100 -22.802 4.417 -10.919 1.00 0.00 <br />
ATOM 756 C ASP A 100 -23.593 3.425 -10.072 1.00 0.00 <br />
ATOM 757 O ASP A 100 -24.371 2.636 -10.609 1.00 0.00 <br />
ATOM 758 CB ASP A 100 -23.724 5.061 -11.962 1.00 0.00 <br />
ATOM 759 CG ASP A 100 -24.763 5.989 -11.343 1.00 0.00 <br />
ATOM 760 OD1 ASP A 100 -25.159 5.770 -10.176 1.00 0.00 <br />
ATOM 761 OD2 ASP A 100 -25.198 6.931 -12.040 1.00 0.00 <br />
ATOM 762 N VAL A 101 -23.385 3.462 -8.761 1.00 0.00 <br />
ATOM 763 CA VAL A 101 -24.031 2.520 -7.849 1.00 0.00 <br />
ATOM 764 C VAL A 101 -24.972 3.155 -6.828 1.00 0.00 <br />
ATOM 765 O VAL A 101 -24.646 4.181 -6.223 1.00 0.00 <br />
ATOM 766 CB VAL A 101 -22.950 1.715 -7.068 1.00 0.00 <br />
ATOM 767 CG1 VAL A 101 -23.601 0.831 -6.002 1.00 0.00 <br />
ATOM 768 CG2 VAL A 101 -22.130 0.866 -8.039 1.00 0.00 <br />
ATOM 769 N GLU A 102 -26.132 2.535 -6.635 1.00 0.00 <br />
ATOM 770 CA GLU A 102 -27.102 3.019 -5.652 1.00 0.00 <br />
ATOM 771 C GLU A 102 -27.435 1.886 -4.674 1.00 0.00 <br />
ATOM 772 O GLU A 102 -27.954 0.845 -5.079 1.00 0.00 <br />
ATOM 773 CB GLU A 102 -28.390 3.503 -6.335 1.00 0.00 <br />
ATOM 774 CG GLU A 102 -29.434 3.975 -5.324 1.00 0.00 <br />
ATOM 775 CD GLU A 102 -30.725 4.468 -5.956 1.00 0.00 <br />
ATOM 776 OE1 GLU A 102 -30.943 4.228 -7.167 1.00 0.00 <br />
ATOM 777 OE2 GLU A 102 -31.531 5.086 -5.224 1.00 0.00 <br />
ATOM 778 N LEU A 103 -27.117 2.088 -3.392 1.00 0.00 <br />
ATOM 779 CA LEU A 103 -27.380 1.085 -2.366 1.00 0.00 <br />
ATOM 780 C LEU A 103 -28.842 1.202 -1.953 1.00 0.00 <br />
ATOM 781 O LEU A 103 -29.199 2.007 -1.094 1.00 0.00 <br />
ATOM 782 CB LEU A 103 -26.468 1.305 -1.156 1.00 0.00 <br />
ATOM 783 CG LEU A 103 -26.609 0.303 -0.005 1.00 0.00 <br />
ATOM 784 CD1 LEU A 103 -26.382 -1.118 -0.505 1.00 0.00 <br />
ATOM 785 CD2 LEU A 103 -25.609 0.653 1.081 1.00 0.00 <br />
ATOM 786 N LEU A 104 -29.675 0.377 -2.570 1.00 0.00 <br />
ATOM 787 CA LEU A 104 -31.111 0.393 -2.332 1.00 0.00 <br />
ATOM 788 C LEU A 104 -31.576 -0.236 -1.027 1.00 0.00 <br />
ATOM 789 O LEU A 104 -32.426 0.320 -0.330 1.00 0.00 <br />
ATOM 790 CB LEU A 104 -31.816 -0.302 -3.490 1.00 0.00 <br />
ATOM 791 CG LEU A 104 -31.473 0.249 -4.875 1.00 0.00 <br />
ATOM 792 CD1 LEU A 104 -31.942 -0.729 -5.949 1.00 0.00 <br />
ATOM 793 CD2 LEU A 104 -32.120 1.615 -5.046 1.00 0.00 <br />
ATOM 794 N ASN A 105 -31.021 -1.393 -0.691 1.00 0.00 <br />
ATOM 795 CA ASN A 105 -31.449 -2.075 0.517 1.00 0.00 <br />
ATOM 796 C ASN A 105 -30.377 -3.035 1.005 1.00 0.00 <br />
ATOM 797 O ASN A 105 -29.434 -3.353 0.276 1.00 0.00 <br />
ATOM 798 CB ASN A 105 -32.746 -2.835 0.206 1.00 0.00 <br />
ATOM 799 CG ASN A 105 -33.449 -3.342 1.448 1.00 0.00 <br />
ATOM 800 OD1 ASN A 105 -33.342 -2.754 2.523 1.00 0.00 <br />
ATOM 801 ND2 ASN A 105 -34.195 -4.431 1.298 1.00 0.00 <br />
ATOM 802 N LEU A 106 -30.524 -3.481 2.248 1.00 0.00 <br />
ATOM 803 CA LEU A 106 -29.600 -4.429 2.856 1.00 0.00 <br />
ATOM 804 C LEU A 106 -30.427 -5.586 3.404 1.00 0.00 <br />
ATOM 805 O LEU A 106 -31.322 -5.377 4.224 1.00 0.00 <br />
ATOM 806 CB LEU A 106 -28.812 -3.754 3.981 1.00 0.00 <br />
ATOM 807 CG LEU A 106 -27.682 -2.843 3.494 1.00 0.00 <br />
ATOM 808 CD1 LEU A 106 -27.164 -1.983 4.632 1.00 0.00 <br />
ATOM 809 CD2 LEU A 106 -26.563 -3.714 2.914 1.00 0.00 <br />
ATOM 810 N GLU A 107 -30.132 -6.800 2.946 1.00 0.00 <br />
ATOM 811 CA GLU A 107 -30.875 -7.980 3.382 1.00 0.00 <br />
ATOM 812 C GLU A 107 -29.979 -9.012 4.061 1.00 0.00 <br />
ATOM 813 O GLU A 107 -28.799 -8.767 4.306 1.00 0.00 <br />
ATOM 814 CB GLU A 107 -31.571 -8.626 2.183 1.00 0.00 <br />
ATOM 815 CG GLU A 107 -32.261 -7.635 1.263 1.00 0.00 <br />
ATOM 816 CD GLU A 107 -32.909 -8.302 0.067 1.00 0.00 <br />
ATOM 817 OE1 GLU A 107 -32.510 -9.436 -0.265 1.00 0.00 <br />
ATOM 818 OE2 GLU A 107 -33.806 -7.687 -0.549 1.00 0.00 <br />
TER<br />
ATOM 819 C1 RAP A 108 -18.510 -8.134 -11.063 1.00 0.00 <br />
ATOM 820 O1 RAP A 108 -18.969 -9.229 -11.856 1.00 0.00 <br />
ATOM 821 O2 RAP A 108 -17.819 -8.381 -10.069 1.00 0.00 <br />
ATOM 822 C2 RAP A 108 -18.857 -6.680 -11.413 1.00 0.00 <br />
ATOM 823 C3 RAP A 108 -19.378 -5.903 -10.192 1.00 0.00 <br />
ATOM 824 C4 RAP A 108 -20.810 -6.269 -9.768 1.00 0.00 <br />
ATOM 825 C5 RAP A 108 -21.748 -6.104 -10.968 1.00 0.00 <br />
ATOM 826 C6 RAP A 108 -21.289 -6.956 -12.126 1.00 0.00 <br />
ATOM 827 N7 RAP A 108 -19.893 -6.531 -12.486 1.00 0.00 <br />
ATOM 828 C8 RAP A 108 -19.513 -6.171 -13.744 1.00 0.00 <br />
ATOM 829 O3 RAP A 108 -18.296 -5.996 -13.976 1.00 0.00 <br />
ATOM 830 C9 RAP A 108 -20.424 -5.985 -14.822 1.00 0.00 <br />
ATOM 831 O4 RAP A 108 -21.015 -4.900 -14.935 1.00 0.00 <br />
ATOM 832 C10 RAP A 108 -20.701 -7.102 -15.860 1.00 0.00 <br />
ATOM 833 O5 RAP A 108 -21.536 -8.043 -15.186 1.00 0.00 <br />
ATOM 834 O6 RAP A 108 -21.405 -6.534 -16.979 1.00 0.00 <br />
ATOM 835 C11 RAP A 108 -19.388 -7.854 -16.375 1.00 0.00 <br />
ATOM 836 C12 RAP A 108 -19.775 -9.075 -17.246 1.00 0.00 <br />
ATOM 837 C13 RAP A 108 -20.761 -9.975 -16.480 1.00 0.00 <br />
ATOM 838 C14 RAP A 108 -21.967 -9.211 -15.854 1.00 0.00 <br />
ATOM 839 C15 RAP A 108 -22.672 -10.085 -14.824 1.00 0.00 <br />
ATOM 840 C16 RAP A 108 -23.453 -11.289 -15.379 1.00 0.00 <br />
ATOM 841 O7 RAP A 108 -24.420 -10.794 -16.279 1.00 0.00 <br />
ATOM 842 C17 RAP A 108 -24.142 -12.089 -14.269 1.00 0.00 <br />
ATOM 843 C18 RAP A 108 -23.665 -13.315 -13.987 1.00 0.00 <br />
ATOM 844 C19 RAP A 108 -24.201 -14.242 -12.966 1.00 0.00 <br />
ATOM 845 C20 RAP A 108 -23.630 -15.435 -12.786 1.00 0.00 <br />
ATOM 846 C21 RAP A 108 -24.162 -16.384 -11.781 1.00 0.00 <br />
ATOM 847 C22 RAP A 108 -23.444 -17.370 -11.268 1.00 0.00 <br />
ATOM 848 C23 RAP A 108 -23.906 -18.220 -10.081 1.00 0.00 <br />
ATOM 849 C24 RAP A 108 -22.851 -18.127 -8.963 1.00 0.00 <br />
ATOM 850 C25 RAP A 108 -22.360 -16.747 -8.519 1.00 0.00 <br />
ATOM 851 C26 RAP A 108 -21.023 -16.845 -7.774 1.00 0.00 <br />
ATOM 852 O8 RAP A 108 -20.965 -16.994 -6.547 1.00 0.00 <br />
ATOM 853 C27 RAP A 108 -19.745 -16.757 -8.633 1.00 0.00 <br />
ATOM 854 O9 RAP A 108 -18.698 -17.397 -7.951 1.00 0.00 <br />
ATOM 855 C28 RAP A 108 -19.234 -15.293 -8.931 1.00 0.00 <br />
ATOM 856 O10 RAP A 108 -19.259 -14.553 -7.701 1.00 0.00 <br />
ATOM 857 C29 RAP A 108 -20.070 -14.540 -10.006 1.00 0.00 <br />
ATOM 858 C30 RAP A 108 -20.851 -13.477 -9.720 1.00 0.00 <br />
ATOM 859 C31 RAP A 108 -21.739 -12.610 -10.632 1.00 0.00 <br />
ATOM 860 C32 RAP A 108 -21.031 -11.274 -10.909 1.00 0.00 <br />
ATOM 861 O11 RAP A 108 -21.295 -10.239 -10.286 1.00 0.00 <br />
ATOM 862 C33 RAP A 108 -19.966 -11.303 -12.008 1.00 0.00 <br />
ATOM 863 C34 RAP A 108 -18.698 -10.575 -11.585 1.00 0.00 <br />
ATOM 864 C35 RAP A 108 -17.359 -10.916 -12.304 1.00 0.00 <br />
ATOM 865 C36 RAP A 108 -16.786 -12.266 -11.815 1.00 0.00 <br />
ATOM 866 C37 RAP A 108 -16.322 -12.376 -10.346 1.00 0.00 <br />
ATOM 867 C38 RAP A 108 -15.790 -13.811 -10.060 1.00 0.00 <br />
ATOM 868 C39 RAP A 108 -15.278 -14.019 -8.595 1.00 0.00 <br />
ATOM 869 O12 RAP A 108 -14.646 -15.301 -8.504 1.00 0.00 <br />
ATOM 870 C40 RAP A 108 -14.253 -12.869 -8.176 1.00 0.00 <br />
ATOM 871 O13 RAP A 108 -14.019 -12.970 -6.766 1.00 0.00 <br />
ATOM 872 C41 RAP A 108 -14.775 -11.432 -8.497 1.00 0.00 <br />
ATOM 873 C42 RAP A 108 -15.251 -11.324 -9.952 1.00 0.00 <br />
ATOM 874 C43 RAP A 108 -18.390 -6.936 -17.162 1.00 0.00 <br />
ATOM 875 C44 RAP A 108 -25.350 -11.389 -13.580 1.00 0.00 <br />
ATOM 876 C45 RAP A 108 -24.081 -19.670 -10.522 1.00 0.00 <br />
ATOM 877 C46 RAP A 108 -23.414 -16.041 -7.644 1.00 0.00 <br />
ATOM 878 C47 RAP A 108 -19.924 -15.115 -11.414 1.00 0.00 <br />
ATOM 879 C48 RAP A 108 -23.101 -12.375 -9.939 1.00 0.00 <br />
ATOM 880 C49 RAP A 108 -17.519 -10.949 -13.817 1.00 0.00 <br />
ATOM 881 C50 RAP A 108 -24.780 -11.612 -17.353 1.00 0.00 <br />
ATOM 882 C51 RAP A 108 -18.394 -18.690 -8.368 1.00 0.00 <br />
ATOM 883 C52 RAP A 108 -13.537 -15.605 -9.312 1.00 0.00 <br />
ATOM 884 O MOL 1 -14.467 -0.075 1.713 1.00 0.00 <br />
ATOM 885 O MOL 1 -3.747 -10.364 -12.950 1.00 0.00 <br />
ATOM 886 O MOL 1 -3.863 1.423 -20.222 1.00 0.00 <br />
ATOM 887 O MOL 1 -33.153 2.955 -17.490 1.00 0.00 <br />
ATOM 888 O MOL 1 -11.437 -10.318 -9.024 1.00 0.00 <br />
ATOM 889 O MOL 1 -8.994 -5.070 -17.002 1.00 0.00 <br />
ATOM 890 O MOL 1 -16.599 7.684 0.589 1.00 0.00 <br />
ATOM 891 O MOL 1 -10.617 -3.779 -15.257 1.00 0.00 <br />
ATOM 892 O MOL 1 -7.744 -0.765 -21.451 1.00 0.00 <br />
ATOM 893 O MOL 1 -30.531 10.772 -1.245 1.00 0.00 <br />
ATOM 894 O MOL 1 -9.991 5.189 -8.561 1.00 0.00 <br />
ATOM 895 O MOL 1 -15.383 8.367 -8.819 1.00 0.00 <br />
ATOM 896 O MOL 1 -22.582 7.719 3.484 1.00 0.00 <br />
ATOM 897 O MOL 1 -31.535 6.282 3.044 1.00 0.00 <br />
ATOM 898 O MOL 1 -6.221 -11.354 -21.344 1.00 0.00 <br />
ATOM 899 O MOL 1 -30.986 8.365 -2.508 1.00 0.00 <br />
ATOM 900 O MOL 1 -26.122 5.808 -14.288 1.00 0.00 <br />
ATOM 901 O MOL 1 -28.681 6.587 -14.636 1.00 0.00 <br />
ATOM 902 O MOL 1 -30.242 9.407 -6.889 1.00 0.00 <br />
ATOM 903 O MOL 1 -4.086 -4.225 -12.418 1.00 0.00 <br />
ATOM 904 O MOL 1 -13.558 9.340 -12.463 1.00 0.00 <br />
ATOM 905 O MOL 1 -24.024 9.804 2.183 1.00 0.00 <br />
ATOM 906 O MOL 1 -28.911 -10.292 -8.292 1.00 0.00 <br />
ATOM 907 O MOL 1 -10.002 -11.107 -20.617 1.00 0.00 <br />
ATOM 908 O MOL 1 -3.379 -1.268 -11.644 1.00 0.00 <br />
ATOM 909 O MOL 1 -3.814 -6.433 -11.116 1.00 0.00 <br />
ATOM 910 O MOL 1 -6.811 1.796 -20.467 1.00 0.00 <br />
ATOM 911 O MOL 1 -5.042 0.450 -5.739 1.00 0.00 <br />
ATOM 912 O MOL 1 -13.226 8.110 -2.465 1.00 0.00 <br />
ATOM 913 O MOL 1 -11.705 -0.385 1.598 1.00 0.00 <br />
ATOM 914 O MOL 1 -26.811 -13.511 -10.984 1.00 0.00 <br />
ATOM 915 O MOL 1 -12.132 3.844 -1.192 1.00 0.00 <br />
ATOM 916 O MOL 1 -12.915 6.445 -0.256 1.00 0.00 <br />
ATOM 917 O MOL 1 -14.006 10.177 -15.559 1.00 0.00 <br />
ATOM 918 O MOL 1 -6.462 2.069 -16.582 1.00 0.00 <br />
ATOM 919 O MOL 1 -21.593 -5.761 -22.112 1.00 0.00 <br />
ATOM 920 O MOL 1 -22.112 4.659 11.361 1.00 0.00 <br />
ATOM 921 O MOL 1 -24.505 -7.743 -19.597 1.00 0.00 <br />
ATOM 922 O MOL 1 -2.660 -0.168 -14.034 1.00 0.00 <br />
ATOM 923 O MOL 1 -2.685 -8.544 -20.622 1.00 0.00 <br />
ATOM 924 O MOL 1 -30.204 4.761 -16.268 1.00 0.00 <br />
ATOM 925 O MOL 1 -1.421 1.865 -16.896 1.00 0.00 <br />
ATOM 926 O MOL 1 -22.558 11.507 0.921 1.00 0.00 <br />
ATOM 927 O MOL 1 -32.805 11.307 0.058 1.00 0.00 <br />
ATOM 928 O MOL 1 -3.446 -8.060 -13.318 1.00 0.00 <br />
ATOM 929 O MOL 1 -29.831 4.936 -9.378 1.00 0.00 <br />
ATOM 930 O MOL 1 -7.164 5.063 -13.547 1.00 0.00 <br />
ATOM 931 O MOL 1 -4.420 2.292 -14.820 1.00 0.00 <br />
ATOM 932 O MOL 1 -5.770 -9.954 -14.183 1.00 0.00 <br />
ATOM 933 O MOL 1 -27.557 -11.487 -9.884 1.00 0.00 <br />
ATOM 934 O MOL 1 -31.664 4.503 -2.445 1.00 0.00 <br />
ATOM 935 O MOL 1 -25.729 -8.264 -16.380 1.00 0.00 <br />
ATOM 936 O MOL 1 -21.969 10.396 5.765 1.00 0.00 <br />
ATOM 937 O MOL 1 -7.004 -0.510 -2.928 1.00 0.00 <br />
ATOM 938 O MOL 1 -30.875 7.805 -13.213 1.00 0.00 <br />
ATOM 939 O MOL 1 -18.401 12.641 -2.383 1.00 0.00 <br />
ATOM 940 O MOL 1 -18.898 -7.605 -25.486 1.00 0.00 <br />
ATOM 941 O MOL 1 -25.575 -5.788 -20.825 1.00 0.00 <br />
ATOM 942 O MOL 1 -7.654 5.064 -6.946 1.00 0.00 <br />
ATOM 943 O MOL 1 -10.256 -9.151 -22.336 1.00 0.00 <br />
ATOM 944 O MOL 1 -19.822 -4.848 -24.124 1.00 0.00 <br />
ATOM 945 O MOL 1 -23.526 -17.086 -4.354 1.00 0.00 <br />
ATOM 946 O MOL 1 -18.719 -10.494 -2.408 1.00 0.00 <br />
ATOM 947 O MOL 1 -17.490 -3.388 -23.343 1.00 0.00 <br />
ATOM 948 O MOL 1 -30.962 10.093 -11.750 1.00 0.00 <br />
ATOM 949 O MOL 1 -18.908 -1.315 -28.688 1.00 0.00 <br />
ATOM 950 O MOL 1 -3.124 -4.146 -15.431 1.00 0.00 <br />
ATOM 951 O MOL 1 -9.221 2.699 -18.647 1.00 0.00 <br />
ATOM 952 O MOL 1 -11.056 -7.239 -8.343 1.00 0.00 <br />
ATOM 953 O MOL 1 -13.633 -12.173 -15.090 1.00 0.00 <br />
ATOM 954 O MOL 1 -15.513 -10.202 -0.432 1.00 0.00 <br />
ATOM 955 O MOL 1 -28.234 2.974 -16.765 1.00 0.00 <br />
ATOM 956 O MOL 1 -15.150 1.628 -25.119 1.00 0.00 <br />
ATOM 957 O MOL 1 -27.057 11.649 5.648 1.00 0.00 <br />
ATOM 958 O MOL 1 -35.417 1.166 -8.176 1.00 0.00 <br />
ATOM 959 O MOL 1 -32.217 9.638 -9.089 1.00 0.00 <br />
ATOM 960 O MOL 1 -19.494 6.929 1.151 1.00 0.00 <br />
ATOM 961 O MOL 1 -9.252 2.616 -2.781 1.00 0.00 <br />
ATOM 962 O MOL 1 -24.348 -8.092 -23.126 1.00 0.00 <br />
ATOM 963 O MOL 1 -21.693 -7.243 -19.749 1.00 0.00 <br />
ATOM 964 O MOL 1 -11.065 8.058 -14.677 1.00 0.00 <br />
ATOM 965 O MOL 1 -21.355 0.992 -27.640 1.00 0.00 <br />
ATOM 966 O MOL 1 -8.191 6.228 -11.230 1.00 0.00 <br />
ATOM 967 O MOL 1 -1.738 -5.828 -9.719 1.00 0.00 <br />
ATOM 968 O MOL 1 -5.954 3.838 -4.110 1.00 0.00 <br />
ATOM 969 O MOL 1 -0.305 -0.954 -13.761 1.00 0.00 <br />
ATOM 970 O MOL 1 -35.121 9.765 -8.231 1.00 0.00 <br />
ATOM 971 O MOL 1 -9.195 7.921 -12.896 1.00 0.00 <br />
ATOM 972 O MOL 1 -11.412 -8.346 -24.443 1.00 0.00 <br />
ATOM 973 O MOL 1 -18.575 -4.730 5.949 1.00 0.00 <br />
ATOM 974 O MOL 1 -24.572 -2.651 -22.639 1.00 0.00 <br />
ATOM 975 O MOL 1 -17.538 -17.548 -1.182 1.00 0.00 <br />
ATOM 976 O MOL 1 -28.405 1.980 11.352 1.00 0.00 <br />
ATOM 977 O MOL 1 -27.591 2.765 -19.420 1.00 0.00 <br />
ATOM 978 O MOL 1 -17.468 7.579 -21.396 1.00 0.00 <br />
ATOM 979 O MOL 1 -31.391 9.463 3.968 1.00 0.00 <br />
ATOM 980 O MOL 1 -24.855 11.287 4.464 1.00 0.00 <br />
ATOM 981 O MOL 1 -32.329 -2.161 4.687 1.00 0.00 <br />
ATOM 982 O MOL 1 -31.502 -1.553 7.124 1.00 0.00 <br />
ATOM 983 O MOL 1 -5.167 -3.927 -5.363 1.00 0.00 <br />
ATOM 984 O MOL 1 -12.442 -12.583 -11.643 1.00 0.00 <br />
TER</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin </font size></font color> <sup>6,7</sup><br />
<br><br />
<br />
Rapamycin is a very complicated molecule. It had a 31 memembered ring, and also possesses many chiral centres, and different functional groups. Due to its complexity, it has proved a challenge to synthesise for many synthetic chemists. <br />
Methods have therefore been suggested, to prepare fragments of the molecule, and then combine them to get the total molecule of rapamycin.<br />
<br />
The first fragment prepared is the fragment from C<sub>10</sub> to C<sub>21</sub>. <br />
The starting material used is (R)-methyl 3-hydroxy-2-methylpropionate. This is converted to an alcohol in a four step reaction, as shown below:<br />
<br />
[[Image:synthesisstep.gif]]<br />
<br />
<br />
Then from this molecule, further complicated synthesis steps yield the following fragment:<br />
<br />
[[Image:Fragment1.gif]]<br />
<br />
<br />
The second fragment prepared is the fragment from C<sub>22</sub> - C<sub>42</sub>. This is prepared through complicated synthetic methods. The second fragment obtained is shown below:<br />
<br />
[[Image:Fragment2.gif]]<br />
<br />
The second fragment was then combined with the first fragment under certain required conditions, yielding the synthetic rapamycin, which was judged as identical to the natural occuring rapamycin molecule through comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.<br />
<br />
The various complicated synthesis steps, and conditions are all in the cited journals, from which this all synthetic information was gained.<br />
<br />
Rapamycin can also be synthesised by using trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH<sub>3</sub>CN)<sub>2</sub> C<sub>12</sub>, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
However, the starting material is hard to synthesise, so is usually only the fragment method of synthesis is used for synthetic rapamycin production<br />
<br />
<br />
<font size=5><font color=red>History</font size></font color><sup>10</sup><br><br />
<br><br />
Rapamycin is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a polyketide pathway. The polyketide chain is formed by condensation of seven acetate components and same number of propionate units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<jmol><br />
<jmolApplet><br />
<size>400</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY QEKNID<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 20.690 22.560 11.220 90.00 90.00 90.00 P 21 21 21 4<br />
ATOM 1 O1 UNK 0 1 1.401 8.009 6.161 1.00 0.00<br />
ATOM 2 O2 UNK 0 1 1.535 9.421 3.430 1.00 0.00<br />
ATOM 3 O3 UNK 0 1 4.165 9.543 3.068 1.00 0.00<br />
ATOM 4 O4 UNK 0 1 6.290 5.800 0.411 1.00 0.00<br />
ATOM 5 O5 UNK 0 1 3.617 0.984 6.788 1.00 0.00<br />
ATOM 6 O6 UNK 0 1 1.988 4.661 5.821 1.00 0.00<br />
ATOM 7 O7 UNK 0 1 3.414 10.078 11.631 1.00 0.00<br />
ATOM 8 O8 UNK 0 1 4.926 9.642 9.448 1.00 0.00<br />
ATOM 9 O9 UNK 0 1 0.134 3.788 6.711 1.00 0.00<br />
ATOM 10 O10 UNK 0 1 8.545 -2.658 8.213 1.00 0.00<br />
ATOM 11 O11 UNK 0 1 3.877 7.255 3.373 1.00 0.00<br />
ATOM 12 O12 UNK 0 1 8.348 1.263 9.851 1.00 0.00<br />
ATOM 13 O13 UNK 0 1 9.710 -0.957 9.885 1.00 0.00<br />
ATOM 14 N1 UNK 0 1 0.821 6.574 4.485 1.00 0.00<br />
ATOM 15 C1 UNK 0 1 2.847 3.804 6.597 1.00 0.00<br />
ATOM 16 C2 UNK 0 1 2.137 8.591 4.006 1.00 0.00<br />
ATOM 17 C3 UNK 0 1 5.253 5.566 2.525 1.00 0.00<br />
ATOM 18 C4 UNK 0 1 6.439 0.772 7.035 1.00 0.00<br />
ATOM 19 C5 UNK 0 1 5.760 1.455 5.879 1.00 0.00<br />
ATOM 20 C6 UNK 0 1 3.691 8.555 3.927 1.00 0.00<br />
ATOM 21 C7 UNK 0 1 4.372 8.706 5.296 1.00 0.00<br />
ATOM 22 C8 UNK 0 1 0.685 4.598 6.025 1.00 0.00<br />
ATOM 23 C9 UNK 0 1 1.444 7.657 4.993 1.00 0.00<br />
ATOM 24 C10 UNK 0 1 5.266 6.987 3.074 1.00 0.00<br />
ATOM 25 C11 UNK 0 1 9.484 1.514 2.917 1.00 0.00<br />
ATOM 26 C12 UNK 0 1 6.546 5.254 1.728 1.00 0.00<br />
ATOM 27 C13 UNK 0 1 0.002 5.764 5.363 1.00 0.00<br />
ATOM 28 C14 UNK 0 1 6.873 3.770 1.616 1.00 0.00<br />
ATOM 29 C15 UNK 0 1 5.845 8.444 5.027 1.00 0.00<br />
ATOM 30 C16 UNK 0 1 4.643 3.941 8.471 1.00 0.00<br />
ATOM 31 C17 UNK 0 1 4.175 10.062 5.891 1.00 0.00<br />
ATOM 32 C18 UNK 0 1 6.062 7.106 4.353 1.00 0.00<br />
ATOM 33 C19 UNK 0 1 1.130 5.996 3.130 1.00 0.00<br />
ATOM 34 C20 UNK 0 1 0.132 5.568 2.424 1.00 0.00<br />
ATOM 35 C21 UNK 0 1 -0.902 4.584 3.310 1.00 0.00<br />
ATOM 36 C22 UNK 0 1 -1.283 5.277 4.634 1.00 0.00<br />
ATOM 37 C23 UNK 0 1 7.333 5.703 -0.449 1.00 0.00<br />
ATOM 38 C24 UNK 0 1 5.787 2.858 0.987 1.00 0.00<br />
ATOM 39 C25 UNK 0 1 4.223 8.521 10.019 1.00 0.00<br />
ATOM 40 C26 UNK 0 1 3.070 9.096 10.659 1.00 0.00<br />
ATOM 41 C27 UNK 0 1 2.162 8.038 11.321 1.00 0.00<br />
ATOM 42 C28 UNK 0 1 1.777 7.000 10.322 1.00 0.00<br />
ATOM 43 C29 UNK 0 1 3.035 6.371 9.593 1.00 0.00<br />
ATOM 44 C30 UNK 0 1 3.813 7.463 8.954 1.00 0.00<br />
ATOM 45 C31 UNK 0 1 4.299 1.800 6.149 1.00 0.00<br />
ATOM 46 C32 UNK 0 1 3.745 3.070 5.621 1.00 0.00<br />
ATOM 47 C33 UNK 0 1 2.489 5.369 8.538 1.00 0.00<br />
ATOM 48 C34 UNK 0 1 3.534 4.692 7.641 1.00 0.00<br />
ATOM 49 C35 UNK 0 1 8.028 3.321 2.132 1.00 0.00<br />
ATOM 50 C36 UNK 0 1 8.423 1.922 2.255 1.00 0.00<br />
ATOM 51 C37 UNK 0 1 10.751 -0.223 3.994 1.00 0.00<br />
ATOM 52 C38 UNK 0 1 10.968 -1.676 4.387 1.00 0.00<br />
ATOM 53 C39 UNK 0 1 12.420 -1.994 4.107 1.00 0.00<br />
ATOM 54 C40 UNK 0 1 10.657 -1.852 5.891 1.00 0.00<br />
ATOM 55 C41 UNK 0 1 9.215 -1.475 6.205 1.00 0.00<br />
ATOM 56 C42 UNK 0 1 9.846 0.140 3.119 1.00 0.00<br />
ATOM 57 C43 UNK 0 1 8.266 -2.391 5.430 1.00 0.00<br />
ATOM 58 C44 UNK 0 1 9.019 -1.694 7.697 1.00 0.00<br />
ATOM 59 C45 UNK 0 1 8.460 2.175 7.057 1.00 0.00<br />
ATOM 60 C46 UNK 0 1 6.296 9.389 9.133 1.00 0.00<br />
ATOM 61 C47 UNK 0 1 9.362 -0.492 8.583 1.00 0.00<br />
ATOM 62 C48 UNK 0 1 10.976 -0.887 10.210 1.00 0.00<br />
ATOM 63 C49 UNK 0 1 8.108 0.334 8.785 1.00 0.00<br />
ATOM 64 C50 UNK 0 1 7.606 1.060 7.562 1.00 0.00<br />
ATOM 65 C51 UNK 0 1 5.843 0.575 4.600 1.00 0.00<br />
ATOM 66 H1 UNK 0 1 3.540 9.985 2.615 1.00 0.00<br />
ATOM 67 H2 UNK 0 1 8.210 2.112 9.513 1.00 0.00<br />
ATOM 68 H3 UNK 0 1 5.710 0.147 7.313 1.00 0.00<br />
ATOM 69 H4 UNK 0 1 6.224 2.351 5.476 1.00 0.00<br />
ATOM 70 H5 UNK 0 1 4.030 7.758 6.075 1.00 0.00<br />
ATOM 71 H6 UNK 0 1 10.151 2.085 3.193 1.00 0.00<br />
ATOM 72 H7 UNK 0 1 6.188 9.139 4.429 1.00 0.00<br />
ATOM 73 H8 UNK 0 1 4.260 3.370 9.108 1.00 0.00<br />
ATOM 74 H9 UNK 0 1 3.269 10.154 6.217 1.00 0.00<br />
ATOM 75 H10 UNK 0 1 6.999 6.982 4.170 1.00 0.00<br />
ATOM 76 H11 UNK 0 1 1.572 6.664 2.602 1.00 0.00<br />
ATOM 77 H12 UNK 0 1 -1.748 4.645 5.196 1.00 0.00<br />
ATOM 78 H13 UNK 0 1 5.371 3.343 0.286 1.00 0.00<br />
ATOM 79 H14 UNK 0 1 1.608 6.177 10.770 1.00 0.00<br />
ATOM 80 H15 UNK 0 1 3.428 5.947 10.188 1.00 0.00<br />
ATOM 81 H16 UNK 0 1 4.802 7.221 8.586 1.00 0.00<br />
ATOM 82 H17 UNK 0 1 3.548 7.930 8.237 1.00 0.00<br />
ATOM 83 H18 UNK 0 1 3.271 2.897 4.825 1.00 0.00<br />
ATOM 84 H19 UNK 0 1 1.879 5.827 7.973 1.00 0.00<br />
ATOM 85 H20 UNK 0 1 3.960 5.331 7.139 1.00 0.00<br />
ATOM 86 H21 UNK 0 1 8.382 3.858 2.781 1.00 0.00<br />
ATOM 87 H22 UNK 0 1 10.258 -2.409 3.883 1.00 0.00<br />
ATOM 88 H23 UNK 0 1 12.704 -2.786 4.518 1.00 0.00<br />
ATOM 89 H24 UNK 0 1 10.659 -2.732 5.892 1.00 0.00<br />
ATOM 90 H25 UNK 0 1 11.239 -1.078 6.572 1.00 0.00<br />
ATOM 91 H26 UNK 0 1 9.195 -0.305 5.991 1.00 0.00<br />
ATOM 92 H27 UNK 0 1 9.112 -0.650 2.517 1.00 0.00<br />
ATOM 93 H28 UNK 0 1 8.466 -3.298 5.647 1.00 0.00<br />
ATOM 94 H29 UNK 0 1 8.322 2.955 7.548 1.00 0.00<br />
ATOM 95 H30 UNK 0 1 6.714 10.132 8.706 1.00 0.00<br />
ATOM 96 H31 UNK 0 1 6.391 8.622 8.547 1.00 0.00<br />
ATOM 97 H32 UNK 0 1 7.293 -0.210 9.074 1.00 0.00<br />
ATOM 98 H33 UNK 0 1 5.866 -0.356 4.865 1.00 0.00<br />
ATOM 99 H34 UNK 0 1 5.183 4.941 3.258 1.00 0.00<br />
ATOM 100 H35 UNK 0 1 7.519 4.789 -0.649 1.00 0.00<br />
ATOM 101 H36 UNK 0 1 7.190 6.184 -1.241 1.00 0.00<br />
ATOM 102 H37 UNK 0 1 1.328 7.208 9.650 1.00 0.00<br />
ATOM 103 H38 UNK 0 1 8.011 1.087 1.694 1.00 0.00<br />
ATOM 104 H39 UNK 0 1 12.617 -2.003 3.181 1.00 0.00<br />
ATOM 105 H40 UNK 0 1 7.366 -2.209 5.718 1.00 0.00<br />
ATOM 106 H41 UNK 0 1 11.307 0.449 4.388 1.00 0.00<br />
ATOM 107 H42 UNK 0 1 -0.679 6.317 2.243 1.00 0.00<br />
ATOM 108 H43 UNK 0 1 0.095 5.141 1.592 1.00 0.00<br />
ATOM 109 H44 UNK 0 1 5.144 2.624 1.641 1.00 0.00<br />
ATOM 110 H45 UNK 0 1 6.209 2.089 0.650 1.00 0.00<br />
ATOM 111 H46 UNK 0 1 -1.872 6.010 4.470 1.00 0.00<br />
ATOM 112 H47 UNK 0 1 1.713 5.252 3.228 1.00 0.00<br />
ATOM 113 H48 UNK 0 1 -0.294 6.351 6.059 1.00 0.00<br />
ATOM 114 H49 UNK 0 1 5.175 3.393 7.855 1.00 0.00<br />
ATOM 115 H50 UNK 0 1 5.228 4.559 8.877 1.00 0.00<br />
ATOM 116 H51 UNK 0 1 2.023 4.681 9.009 1.00 0.00<br />
ATOM 117 H52 UNK 0 1 1.378 8.478 11.672 1.00 0.00<br />
ATOM 118 H53 UNK 0 1 2.549 9.527 9.980 1.00 0.00<br />
ATOM 119 H54 UNK 0 1 4.759 8.106 10.676 1.00 0.00<br />
ATOM 120 H55 UNK 0 1 6.811 9.184 9.931 1.00 0.00<br />
ATOM 121 H56 UNK 0 1 3.064 10.019 12.513 1.00 0.00<br />
ATOM 122 H57 UNK 0 1 5.046 0.704 4.082 1.00 0.00<br />
ATOM 123 H58 UNK 0 1 6.596 0.778 4.098 1.00 0.00<br />
ATOM 124 H59 UNK 0 1 9.391 1.922 7.099 1.00 0.00<br />
ATOM 125 H60 UNK 0 1 8.249 2.330 6.128 1.00 0.00<br />
ATOM 126 H61 UNK 0 1 11.301 -0.034 10.172 1.00 0.00<br />
ATOM 127 H62 UNK 0 1 8.344 -2.245 4.515 1.00 0.00<br />
ATOM 128 H63 UNK 0 1 12.991 -1.261 4.491 1.00 0.00<br />
ATOM 129 H64 UNK 0 1 7.291 5.701 2.119 1.00 0.00<br />
ATOM 130 H65 UNK 0 1 4.496 5.446 1.961 1.00 0.00<br />
ATOM 131 H66 UNK 0 1 5.609 7.596 2.424 1.00 0.00<br />
ATOM 132 H67 UNK 0 1 6.352 8.496 5.832 1.00 0.00<br />
ATOM 133 H68 UNK 0 1 4.769 10.215 6.611 1.00 0.00<br />
ATOM 134 H69 UNK 0 1 4.308 10.741 5.225 1.00 0.00<br />
ATOM 135 H70 UNK 0 1 2.319 3.147 7.060 1.00 0.00<br />
ATOM 136 H71 UNK 0 1 5.793 6.418 4.966 1.00 0.00<br />
ATOM 137 H72 UNK 0 1 -1.823 4.302 2.821 1.00 0.00<br />
ATOM 138 H73 UNK 0 1 -0.339 3.831 3.457 1.00 0.00<br />
ATOM 139 H74 UNK 0 1 8.137 6.064 -0.019 1.00 0.00<br />
ATOM 140 H75 UNK 0 1 2.630 7.650 12.060 1.00 0.00<br />
ATOM 141 H76 UNK 0 1 4.498 3.646 5.411 1.00 0.00<br />
ATOM 142 H77 UNK 0 1 11.137 -1.200 11.098 1.00 0.00<br />
ATOM 143 H78 UNK 0 1 11.531 -1.392 9.609 1.00 0.00<br />
ATOM 144 H79 UNK 0 1 10.095 0.059 8.192 1.00 0.00<br />
ATOM 145 H80 UNK 0 1 6.443 3.641 2.498 1.00 0.00<br />
CONECT 1 23<br />
CONECT 2 16<br />
CONECT 3 20 66<br />
CONECT 4 26 37<br />
CONECT 5 45<br />
CONECT 6 15 22<br />
CONECT 7 40 121<br />
CONECT 8 39 60<br />
CONECT 9 22<br />
CONECT 10 58<br />
CONECT 11 20 24<br />
CONECT 12 63 67<br />
CONECT 13 61 62<br />
CONECT 14 23 27 33<br />
CONECT 15 6 46 48 135<br />
CONECT 16 2 20 23<br />
CONECT 17 24 26 99 130<br />
CONECT 18 19 64 68<br />
CONECT 19 18 45 65 69<br />
CONECT 20 3 11 16 21<br />
CONECT 21 20 29 31 70<br />
CONECT 22 6 9 27<br />
CONECT 23 1 14 16<br />
CONECT 24 11 17 32 131<br />
CONECT 25 50 56 71<br />
CONECT 26 4 17 28 129<br />
CONECT 27 14 22 36 113<br />
CONECT 28 26 38 49<br />
CONECT 29 21 32 72 132<br />
CONECT 30 48 73 114 115<br />
CONECT 31 21 74 133 134<br />
CONECT 32 24 29 75 136<br />
CONECT 33 14 34 76 112<br />
CONECT 34 33 35 107 108<br />
CONECT 35 34 36 137 138<br />
CONECT 36 27 35 77 111<br />
CONECT 37 4 100 101 139<br />
CONECT 38 28 78 109 110<br />
CONECT 39 8 40 44 119<br />
CONECT 40 7 39 41 118<br />
CONECT 41 40 42 117 140<br />
CONECT 42 41 43 79 102<br />
CONECT 43 42 44 47 80<br />
CONECT 44 39 43 81 82<br />
CONECT 45 5 19 46<br />
CONECT 46 15 45 83 141<br />
CONECT 47 43 48 84 116<br />
CONECT 48 15 30 47 85<br />
CONECT 49 28 50 86<br />
CONECT 50 25 49 103<br />
CONECT 51 52 56 106<br />
CONECT 52 51 53 54 87<br />
CONECT 53 52 88 104 128<br />
CONECT 54 52 55 89 90<br />
CONECT 55 54 57 58 91<br />
CONECT 56 25 51 92<br />
CONECT 57 55 93 105 127<br />
CONECT 58 10 55 61<br />
CONECT 59 64 94 124 125<br />
CONECT 60 8 95 96 120<br />
CONECT 61 13 58 63 144<br />
CONECT 62 13 126 142 143<br />
CONECT 63 12 61 64 97<br />
CONECT 64 18 59 63<br />
CONECT 65 19 98 122 123<br />
CONECT 66 3<br />
CONECT 67 12<br />
CONECT 68 18<br />
CONECT 69 19<br />
CONECT 70 21<br />
CONECT 71 25<br />
CONECT 72 29<br />
CONECT 73 30<br />
CONECT 74 31<br />
CONECT 75 32<br />
CONECT 76 33<br />
CONECT 77 36<br />
CONECT 78 38<br />
CONECT 79 42<br />
CONECT 80 43<br />
CONECT 81 44<br />
CONECT 82 44<br />
CONECT 83 46<br />
CONECT 84 47<br />
CONECT 85 48<br />
CONECT 86 49<br />
CONECT 87 52<br />
CONECT 88 53<br />
CONECT 89 54<br />
CONECT 90 54<br />
CONECT 91 55<br />
CONECT 92 56<br />
CONECT 93 57<br />
CONECT 94 59<br />
CONECT 95 60<br />
CONECT 96 60<br />
CONECT 97 63<br />
CONECT 98 65<br />
CONECT 99 17<br />
CONECT 100 37<br />
CONECT 101 37<br />
CONECT 102 42<br />
CONECT 103 50<br />
CONECT 104 53<br />
CONECT 105 57<br />
CONECT 106 51<br />
CONECT 107 34<br />
CONECT 108 34<br />
CONECT 109 38<br />
CONECT 110 38<br />
CONECT 111 36<br />
CONECT 112 33<br />
CONECT 113 27<br />
CONECT 114 30<br />
CONECT 115 30<br />
CONECT 116 47<br />
CONECT 117 41<br />
CONECT 118 40<br />
CONECT 119 39<br />
CONECT 120 60<br />
CONECT 121 7<br />
CONECT 122 65<br />
CONECT 123 65<br />
CONECT 124 59<br />
CONECT 125 59<br />
CONECT 126 62<br />
CONECT 127 57<br />
CONECT 128 53<br />
CONECT 129 26<br />
CONECT 130 17<br />
CONECT 131 24<br />
CONECT 132 29<br />
CONECT 133 31<br />
CONECT 134 31<br />
CONECT 135 15<br />
CONECT 136 32<br />
CONECT 137 35<br />
CONECT 138 35<br />
CONECT 139 37<br />
CONECT 140 41<br />
CONECT 141 46<br />
CONECT 142 62<br />
CONECT 143 62<br />
CONECT 144 61<br />
CONECT 145 0<br />
MASTER 0 0 0 0 0 0 0 0 145 0 145 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br><br />
6) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato; J. Am. Chem. Soc.; 115; 1993; 4419-4420 <br><br />
7) D. Romo, D. D. Johnson, L. Plamondon, T. Miwa, S. L. Schreiber; J. Org. Chem.; 57; 1992; 5060-5063 <br><br />
8) http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
9) ''How Rapamycin works'' diagram taken from http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
10) http://www.rapamycin.org/rapamycin.html<br><br />
11) ''3D structure of the binding protein, <br />
FKBP 12.6 in complex with a rapamycin molecule'' <br />
image taken from http://www.rcsb.org/pdb/explore.do?structureId=1C9H</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4224
It:Rapamycin
2006-10-26T13:32:21Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:Rapamycin.gif|50|2D structure of Rapamycin|50]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>400</size><br />
<color>black</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
The rapamycin is thought to target the proteins <sup>8</sup>:<br />
(1) 70-kD S6 protein kinase p70<sup>S6K</sup><br />
(2) Eukaryotic initiation factor eIF-4F<br />
(3) G1-controlling cyclin-dependent kinase (cdk) proteins <br />
(4) Kinase inhibitory protein Kip1 (p27<sup>kip</sup>), which blocks cell progression to the S phase.<br />
<br />
The diagram below shows how the mechanism steps of how rapamycin works:<br />
<br />
'''How Rapamycin works'''<br />
[[Image:mechanism.gif]]<br />
<br />
''Note:''<br />
SRL = Sirolimus (rapamycin)<br />
mTOR = mammalian target of rapamycin<br />
CsA = Cyclosporine<br />
PTKs = protein tyrosine kinases<br />
p34<sup>cdc2</sup> = a kinase<br />
<br />
Below is the 3D structure of the binding protein, FKBP 12.6 in complex with a rapamycin molecule: <br />
<br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>black</color><br />
<script>zoom 100; cpk on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>REMARK MSI WebLab Viewer PDB file<br />
REMARK Created: Thu Oct 26 13:37:31 GMT Standard Time 2006<br />
CRYST1 45.696 49.288 51.694 90.00 90.00 90.00 P212121<br />
ATOM 1 N GLY A 1 -6.981 2.196 -6.695 1.00 0.00 <br />
ATOM 2 CA GLY A 1 -8.065 1.703 -5.797 1.00 0.00 <br />
ATOM 3 C GLY A 1 -9.417 2.193 -6.277 1.00 0.00 <br />
ATOM 4 O GLY A 1 -9.620 2.391 -7.474 1.00 0.00 <br />
ATOM 5 N VAL A 2 -10.341 2.395 -5.345 1.00 0.00 <br />
ATOM 6 CA VAL A 2 -11.672 2.874 -5.688 1.00 0.00 <br />
ATOM 7 C VAL A 2 -11.896 4.253 -5.093 1.00 0.00 <br />
ATOM 8 O VAL A 2 -11.650 4.467 -3.906 1.00 0.00 <br />
ATOM 9 CB VAL A 2 -12.775 1.964 -5.119 1.00 0.00 <br />
ATOM 10 CG1 VAL A 2 -14.094 2.249 -5.822 1.00 0.00 <br />
ATOM 11 CG2 VAL A 2 -12.376 0.517 -5.254 1.00 0.00 <br />
ATOM 12 N GLU A 3 -12.355 5.183 -5.923 1.00 0.00 <br />
ATOM 13 CA GLU A 3 -12.654 6.535 -5.471 1.00 0.00 <br />
ATOM 14 C GLU A 3 -14.163 6.708 -5.554 1.00 0.00 <br />
ATOM 15 O GLU A 3 -14.802 6.200 -6.474 1.00 0.00 <br />
ATOM 16 CB GLU A 3 -11.955 7.572 -6.348 1.00 0.00 <br />
ATOM 17 CG GLU A 3 -10.439 7.498 -6.286 1.00 0.00 <br />
ATOM 18 CD GLU A 3 -9.773 8.693 -6.944 1.00 0.00 <br />
ATOM 19 OE1 GLU A 3 -10.120 9.004 -8.106 1.00 0.00 <br />
ATOM 20 OE2 GLU A 3 -8.902 9.321 -6.299 1.00 0.00 <br />
ATOM 21 N ILE A 4 -14.724 7.428 -4.590 1.00 0.00 <br />
ATOM 22 CA ILE A 4 -16.160 7.645 -4.517 1.00 0.00 <br />
ATOM 23 C ILE A 4 -16.539 9.118 -4.648 1.00 0.00 <br />
ATOM 24 O ILE A 4 -15.943 9.977 -4.004 1.00 0.00 <br />
ATOM 25 CB ILE A 4 -16.728 7.152 -3.150 1.00 0.00 <br />
ATOM 26 CG1 ILE A 4 -16.327 5.697 -2.890 1.00 0.00 <br />
ATOM 27 CG2 ILE A 4 -18.232 7.308 -3.120 1.00 0.00 <br />
ATOM 28 CD1 ILE A 4 -16.872 4.708 -3.892 1.00 0.00 <br />
ATOM 29 N GLU A 5 -17.527 9.393 -5.494 1.00 0.00 <br />
ATOM 30 CA GLU A 5 -18.054 10.744 -5.669 1.00 0.00 <br />
ATOM 31 C GLU A 5 -19.552 10.561 -5.505 1.00 0.00 <br />
ATOM 32 O GLU A 5 -20.210 9.962 -6.357 1.00 0.00 <br />
ATOM 33 CB GLU A 5 -17.748 11.307 -7.060 1.00 0.00 <br />
ATOM 34 CG GLU A 5 -16.281 11.588 -7.305 1.00 0.00 <br />
ATOM 35 CD GLU A 5 -16.027 12.152 -8.688 1.00 0.00 <br />
ATOM 36 OE1 GLU A 5 -16.467 13.290 -8.959 1.00 0.00 <br />
ATOM 37 OE2 GLU A 5 -15.390 11.452 -9.505 1.00 0.00 <br />
ATOM 38 N THR A 6 -20.086 11.064 -4.401 1.00 0.00 <br />
ATOM 39 CA THR A 6 -21.503 10.918 -4.115 1.00 0.00 <br />
ATOM 40 C THR A 6 -22.435 11.594 -5.113 1.00 0.00 <br />
ATOM 41 O THR A 6 -22.225 12.741 -5.517 1.00 0.00 <br />
ATOM 42 CB THR A 6 -21.819 11.427 -2.699 1.00 0.00 <br />
ATOM 43 OG1 THR A 6 -21.153 10.595 -1.743 1.00 0.00 <br />
ATOM 44 CG2 THR A 6 -23.321 11.402 -2.440 1.00 0.00 <br />
ATOM 45 N ILE A 7 -23.461 10.853 -5.514 1.00 0.00 <br />
ATOM 46 CA ILE A 7 -24.471 11.341 -6.443 1.00 0.00 <br />
ATOM 47 C ILE A 7 -25.656 11.812 -5.601 1.00 0.00 <br />
ATOM 48 O ILE A 7 -26.213 12.891 -5.818 1.00 0.00 <br />
ATOM 49 CB ILE A 7 -24.909 10.212 -7.401 1.00 0.00 <br />
ATOM 50 CG1 ILE A 7 -23.758 9.896 -8.365 1.00 0.00 <br />
ATOM 51 CG2 ILE A 7 -26.173 10.614 -8.163 1.00 0.00 <br />
ATOM 52 CD1 ILE A 7 -24.015 8.709 -9.281 1.00 0.00 <br />
ATOM 53 N SER A 8 -26.033 10.977 -4.639 1.00 0.00 <br />
ATOM 54 CA SER A 8 -27.119 11.267 -3.707 1.00 0.00 <br />
ATOM 55 C SER A 8 -26.659 10.688 -2.380 1.00 0.00 <br />
ATOM 56 O SER A 8 -26.206 9.549 -2.323 1.00 0.00 <br />
ATOM 57 CB SER A 8 -28.422 10.596 -4.144 1.00 0.00 <br />
ATOM 58 OG SER A 8 -29.022 11.290 -5.223 1.00 0.00 <br />
ATOM 59 N PRO A 9 -26.773 11.462 -1.292 1.00 0.00 <br />
ATOM 60 CA PRO A 9 -26.339 10.972 0.020 1.00 0.00 <br />
ATOM 61 C PRO A 9 -27.220 9.882 0.618 1.00 0.00 <br />
ATOM 62 O PRO A 9 -28.409 9.801 0.324 1.00 0.00 <br />
ATOM 63 CB PRO A 9 -26.321 12.244 0.868 1.00 0.00 <br />
ATOM 64 CG PRO A 9 -27.477 13.024 0.300 1.00 0.00 <br />
ATOM 65 CD PRO A 9 -27.298 12.837 -1.201 1.00 0.00 <br />
ATOM 66 N GLY A 10 -26.617 9.034 1.446 1.00 0.00 <br />
ATOM 67 CA GLY A 10 -27.365 7.973 2.098 1.00 0.00 <br />
ATOM 68 C GLY A 10 -27.791 8.483 3.463 1.00 0.00 <br />
ATOM 69 O GLY A 10 -27.748 9.688 3.707 1.00 0.00 <br />
ATOM 70 N ASP A 11 -28.198 7.595 4.363 1.00 0.00 <br />
ATOM 71 CA ASP A 11 -28.605 8.063 5.682 1.00 0.00 <br />
ATOM 72 C ASP A 11 -27.363 8.404 6.509 1.00 0.00 <br />
ATOM 73 O ASP A 11 -27.462 8.997 7.583 1.00 0.00 <br />
ATOM 74 CB ASP A 11 -29.469 7.014 6.394 1.00 0.00 <br />
ATOM 75 CG ASP A 11 -28.717 5.729 6.695 1.00 0.00 <br />
ATOM 76 OD1 ASP A 11 -27.485 5.676 6.484 1.00 0.00 <br />
ATOM 77 OD2 ASP A 11 -29.373 4.771 7.158 1.00 0.00 <br />
ATOM 78 N GLY A 12 -26.196 8.029 5.990 1.00 0.00 <br />
ATOM 79 CA GLY A 12 -24.941 8.314 6.664 1.00 0.00 <br />
ATOM 80 C GLY A 12 -24.631 7.519 7.920 1.00 0.00 <br />
ATOM 81 O GLY A 12 -23.743 7.898 8.690 1.00 0.00 <br />
ATOM 82 N ARG A 13 -25.335 6.415 8.137 1.00 0.00 <br />
ATOM 83 CA ARG A 13 -25.084 5.619 9.329 1.00 0.00 <br />
ATOM 84 C ARG A 13 -25.326 4.126 9.156 1.00 0.00 <br />
ATOM 85 O ARG A 13 -24.781 3.320 9.907 1.00 0.00 <br />
ATOM 86 CB ARG A 13 -25.919 6.156 10.498 1.00 0.00 <br />
ATOM 87 CG ARG A 13 -27.396 6.326 10.197 1.00 0.00 <br />
ATOM 88 CD ARG A 13 -28.075 7.146 11.295 1.00 0.00 <br />
ATOM 89 NE ARG A 13 -29.469 7.446 10.981 1.00 0.00 <br />
ATOM 90 CZ ARG A 13 -30.430 6.533 10.895 1.00 0.00 <br />
ATOM 91 NH1 ARG A 13 -30.152 5.252 11.103 1.00 0.00 <br />
ATOM 92 NH2 ARG A 13 -31.669 6.897 10.593 1.00 0.00 <br />
ATOM 93 N THR A 14 -26.126 3.755 8.163 1.00 0.00 <br />
ATOM 94 CA THR A 14 -26.420 2.346 7.925 1.00 0.00 <br />
ATOM 95 C THR A 14 -25.571 1.781 6.791 1.00 0.00 <br />
ATOM 96 O THR A 14 -25.933 1.895 5.619 1.00 0.00 <br />
ATOM 97 CB THR A 14 -27.907 2.141 7.586 1.00 0.00 <br />
ATOM 98 OG1 THR A 14 -28.718 2.756 8.599 1.00 0.00 <br />
ATOM 99 CG2 THR A 14 -28.236 0.657 7.519 1.00 0.00 <br />
ATOM 100 N PHE A 15 -24.445 1.166 7.150 1.00 0.00 <br />
ATOM 101 CA PHE A 15 -23.527 0.588 6.174 1.00 0.00 <br />
ATOM 102 C PHE A 15 -23.654 -0.930 6.104 1.00 0.00 <br />
ATOM 103 O PHE A 15 -24.151 -1.569 7.035 1.00 0.00 <br />
ATOM 104 CB PHE A 15 -22.074 0.944 6.521 1.00 0.00 <br />
ATOM 105 CG PHE A 15 -21.800 2.422 6.558 1.00 0.00 <br />
ATOM 106 CD1 PHE A 15 -22.182 3.186 7.656 1.00 0.00 <br />
ATOM 107 CD2 PHE A 15 -21.176 3.052 5.488 1.00 0.00 <br />
ATOM 108 CE1 PHE A 15 -21.943 4.564 7.689 1.00 0.00 <br />
ATOM 109 CE2 PHE A 15 -20.933 4.429 5.508 1.00 0.00 <br />
ATOM 110 CZ PHE A 15 -21.318 5.184 6.614 1.00 0.00 <br />
ATOM 111 N PRO A 16 -23.198 -1.529 4.994 1.00 0.00 <br />
ATOM 112 CA PRO A 16 -23.272 -2.984 4.832 1.00 0.00 <br />
ATOM 113 C PRO A 16 -22.464 -3.715 5.904 1.00 0.00 <br />
ATOM 114 O PRO A 16 -21.291 -3.410 6.120 1.00 0.00 <br />
ATOM 115 CB PRO A 16 -22.694 -3.205 3.433 1.00 0.00 <br />
ATOM 116 CG PRO A 16 -23.072 -1.940 2.713 1.00 0.00 <br />
ATOM 117 CD PRO A 16 -22.744 -0.887 3.748 1.00 0.00 <br />
ATOM 118 N LYS A 17 -23.102 -4.668 6.578 1.00 0.00 <br />
ATOM 119 CA LYS A 17 -22.435 -5.451 7.614 1.00 0.00 <br />
ATOM 120 C LYS A 17 -21.978 -6.781 7.019 1.00 0.00 <br />
ATOM 121 O LYS A 17 -22.447 -7.190 5.959 1.00 0.00 <br />
ATOM 122 CB LYS A 17 -23.385 -5.729 8.782 1.00 0.00 <br />
ATOM 123 CG LYS A 17 -23.891 -4.500 9.515 1.00 0.00 <br />
ATOM 124 CD LYS A 17 -24.763 -4.914 10.696 1.00 0.00 <br />
ATOM 125 CE LYS A 17 -25.272 -3.707 11.472 1.00 0.00 <br />
ATOM 126 NZ LYS A 17 -26.068 -4.106 12.674 1.00 0.00 <br />
ATOM 127 N LYS A 18 -21.072 -7.460 7.713 1.00 0.00 <br />
ATOM 128 CA LYS A 18 -20.565 -8.745 7.243 1.00 0.00 <br />
ATOM 129 C LYS A 18 -21.705 -9.742 7.046 1.00 0.00 <br />
ATOM 130 O LYS A 18 -22.583 -9.871 7.896 1.00 0.00 <br />
ATOM 131 CB LYS A 18 -19.559 -9.310 8.247 1.00 0.00 <br />
ATOM 132 CG LYS A 18 -18.379 -8.395 8.523 1.00 0.00 <br />
ATOM 133 CD LYS A 18 -17.434 -9.010 9.547 1.00 0.00 <br />
ATOM 134 CE LYS A 18 -16.263 -8.085 9.851 1.00 0.00 <br />
ATOM 135 NZ LYS A 18 -15.335 -8.691 10.844 1.00 0.00 <br />
ATOM 136 N GLY A 19 -21.692 -10.435 5.912 1.00 0.00 <br />
ATOM 137 CA GLY A 19 -22.726 -11.418 5.637 1.00 0.00 <br />
ATOM 138 C GLY A 19 -24.002 -10.886 5.009 1.00 0.00 <br />
ATOM 139 O GLY A 19 -24.752 -11.645 4.390 1.00 0.00 <br />
ATOM 140 N GLN A 20 -24.262 -9.590 5.165 1.00 0.00 <br />
ATOM 141 CA GLN A 20 -25.464 -8.992 4.596 1.00 0.00 <br />
ATOM 142 C GLN A 20 -25.453 -9.062 3.079 1.00 0.00 <br />
ATOM 143 O GLN A 20 -24.400 -9.216 2.457 1.00 0.00 <br />
ATOM 144 CB GLN A 20 -25.602 -7.527 5.016 1.00 0.00 <br />
ATOM 145 CG GLN A 20 -26.018 -7.319 6.456 1.00 0.00 <br />
ATOM 146 CD GLN A 20 -26.535 -5.914 6.703 1.00 0.00 <br />
ATOM 147 OE1 GLN A 20 -25.795 -4.937 6.592 1.00 0.00 <br />
ATOM 148 NE2 GLN A 20 -27.818 -5.806 7.030 1.00 0.00 <br />
ATOM 149 N THR A 21 -26.637 -8.950 2.490 1.00 0.00 <br />
ATOM 150 CA THR A 21 -26.773 -8.978 1.043 1.00 0.00 <br />
ATOM 151 C THR A 21 -27.114 -7.571 0.582 1.00 0.00 <br />
ATOM 152 O THR A 21 -28.130 -7.004 0.990 1.00 0.00 <br />
ATOM 153 CB THR A 21 -27.896 -9.934 0.592 1.00 0.00 <br />
ATOM 154 OG1 THR A 21 -27.606 -11.263 1.044 1.00 0.00 <br />
ATOM 155 CG2 THR A 21 -28.009 -9.935 -0.922 1.00 0.00 <br />
ATOM 156 N CYS A 22 -26.250 -7.002 -0.251 1.00 0.00 <br />
ATOM 157 CA CYS A 22 -26.479 -5.662 -0.765 1.00 0.00 <br />
ATOM 158 C CYS A 22 -27.405 -5.709 -1.970 1.00 0.00 <br />
ATOM 159 O CYS A 22 -27.232 -6.537 -2.866 1.00 0.00 <br />
ATOM 160 CB CYS A 22 -25.155 -5.012 -1.172 1.00 0.00 <br />
ATOM 161 SG CYS A 22 -24.056 -4.617 0.206 1.00 0.00 <br />
ATOM 162 N VAL A 23 -28.405 -4.835 -1.972 1.00 0.00 <br />
ATOM 163 CA VAL A 23 -29.329 -4.740 -3.093 1.00 0.00 <br />
ATOM 164 C VAL A 23 -28.961 -3.414 -3.736 1.00 0.00 <br />
ATOM 165 O VAL A 23 -29.121 -2.349 -3.137 1.00 0.00 <br />
ATOM 166 CB VAL A 23 -30.798 -4.711 -2.640 1.00 0.00 <br />
ATOM 167 CG1 VAL A 23 -31.710 -4.703 -3.861 1.00 0.00 <br />
ATOM 168 CG2 VAL A 23 -31.097 -5.921 -1.758 1.00 0.00 <br />
ATOM 169 N VAL A 24 -28.458 -3.489 -4.958 1.00 0.00 <br />
ATOM 170 CA VAL A 24 -28.003 -2.305 -5.665 1.00 0.00 <br />
ATOM 171 C VAL A 24 -28.488 -2.194 -7.105 1.00 0.00 <br />
ATOM 172 O VAL A 24 -28.914 -3.174 -7.716 1.00 0.00 <br />
ATOM 173 CB VAL A 24 -26.449 -2.289 -5.700 1.00 0.00 <br />
ATOM 174 CG1 VAL A 24 -25.945 -1.234 -6.669 1.00 0.00 <br />
ATOM 175 CG2 VAL A 24 -25.897 -2.045 -4.307 1.00 0.00 <br />
ATOM 176 N HIS A 25 -28.430 -0.973 -7.624 1.00 0.00 <br />
ATOM 177 CA HIS A 25 -28.737 -0.711 -9.015 1.00 0.00 <br />
ATOM 178 C HIS A 25 -27.410 -0.147 -9.512 1.00 0.00 <br />
ATOM 179 O HIS A 25 -26.775 0.644 -8.817 1.00 0.00 <br />
ATOM 180 CB HIS A 25 -29.841 0.328 -9.171 1.00 0.00 <br />
ATOM 181 CG HIS A 25 -31.102 -0.227 -9.753 1.00 0.00 <br />
ATOM 182 ND1 HIS A 25 -31.106 -1.070 -10.844 1.00 0.00 <br />
ATOM 183 CD2 HIS A 25 -32.399 -0.061 -9.401 1.00 0.00 <br />
ATOM 184 CE1 HIS A 25 -32.350 -1.399 -11.138 1.00 0.00 <br />
ATOM 185 NE2 HIS A 25 -33.154 -0.801 -10.278 1.00 0.00 <br />
ATOM 186 N TYR A 26 -26.967 -0.558 -10.691 1.00 0.00 <br />
ATOM 187 CA TYR A 26 -25.700 -0.054 -11.189 1.00 0.00 <br />
ATOM 188 C TYR A 26 -25.663 0.063 -12.704 1.00 0.00 <br />
ATOM 189 O TYR A 26 -26.477 -0.525 -13.415 1.00 0.00 <br />
ATOM 190 CB TYR A 26 -24.557 -0.970 -10.723 1.00 0.00 <br />
ATOM 191 CG TYR A 26 -24.487 -2.281 -11.480 1.00 0.00 <br />
ATOM 192 CD1 TYR A 26 -23.818 -2.367 -12.703 1.00 0.00 <br />
ATOM 193 CD2 TYR A 26 -25.132 -3.423 -11.002 1.00 0.00 <br />
ATOM 194 CE1 TYR A 26 -23.791 -3.555 -13.431 1.00 0.00 <br />
ATOM 195 CE2 TYR A 26 -25.118 -4.617 -11.726 1.00 0.00 <br />
ATOM 196 CZ TYR A 26 -24.445 -4.673 -12.942 1.00 0.00 <br />
ATOM 197 OH TYR A 26 -24.434 -5.841 -13.671 1.00 0.00 <br />
ATOM 198 N THR A 27 -24.697 0.840 -13.174 1.00 0.00 <br />
ATOM 199 CA THR A 27 -24.449 1.055 -14.587 1.00 0.00 <br />
ATOM 200 C THR A 27 -22.928 1.057 -14.665 1.00 0.00 <br />
ATOM 201 O THR A 27 -22.264 1.819 -13.956 1.00 0.00 <br />
ATOM 202 CB THR A 27 -24.992 2.416 -15.072 1.00 0.00 <br />
ATOM 203 OG1 THR A 27 -26.420 2.441 -14.928 1.00 0.00 <br />
ATOM 204 CG2 THR A 27 -24.624 2.646 -16.535 1.00 0.00 <br />
ATOM 205 N GLY A 28 -22.382 0.180 -15.501 1.00 0.00 <br />
ATOM 206 CA GLY A 28 -20.939 0.086 -15.638 1.00 0.00 <br />
ATOM 207 C GLY A 28 -20.472 0.667 -16.951 1.00 0.00 <br />
ATOM 208 O GLY A 28 -21.100 0.468 -17.994 1.00 0.00 <br />
ATOM 209 N MET A 29 -19.352 1.371 -16.908 1.00 0.00 <br />
ATOM 210 CA MET A 29 -18.826 2.009 -18.101 1.00 0.00 <br />
ATOM 211 C MET A 29 -17.303 2.036 -18.084 1.00 0.00 <br />
ATOM 212 O MET A 29 -16.690 2.198 -17.028 1.00 0.00 <br />
ATOM 213 CB MET A 29 -19.385 3.432 -18.163 1.00 0.00 <br />
ATOM 214 CG MET A 29 -18.848 4.325 -19.251 1.00 0.00 <br />
ATOM 215 SD MET A 29 -19.532 5.992 -19.016 1.00 0.00 <br />
ATOM 216 CE MET A 29 -18.323 6.720 -17.930 1.00 0.00 <br />
ATOM 217 N LEU A 30 -16.690 1.861 -19.248 1.00 0.00 <br />
ATOM 218 CA LEU A 30 -15.235 1.913 -19.343 1.00 0.00 <br />
ATOM 219 C LEU A 30 -14.853 3.387 -19.268 1.00 0.00 <br />
ATOM 220 O LEU A 30 -15.529 4.229 -19.857 1.00 0.00 <br />
ATOM 221 CB LEU A 30 -14.762 1.331 -20.679 1.00 0.00 <br />
ATOM 222 CG LEU A 30 -15.062 -0.143 -20.933 1.00 0.00 <br />
ATOM 223 CD1 LEU A 30 -14.700 -0.502 -22.371 1.00 0.00 <br />
ATOM 224 CD2 LEU A 30 -14.275 -0.990 -19.947 1.00 0.00 <br />
ATOM 225 N GLN A 31 -13.789 3.714 -18.543 1.00 0.00 <br />
ATOM 226 CA GLN A 31 -13.381 5.111 -18.432 1.00 0.00 <br />
ATOM 227 C GLN A 31 -13.116 5.621 -19.841 1.00 0.00 <br />
ATOM 228 O GLN A 31 -12.319 5.033 -20.568 1.00 0.00 <br />
ATOM 229 CB GLN A 31 -12.107 5.249 -17.595 1.00 0.00 <br />
ATOM 230 CG GLN A 31 -11.789 6.685 -17.216 1.00 0.00 <br />
ATOM 231 CD GLN A 31 -10.349 6.885 -16.801 1.00 0.00 <br />
ATOM 232 OE1 GLN A 31 -9.782 6.078 -16.073 1.00 0.00 <br />
ATOM 233 NE2 GLN A 31 -9.755 7.990 -17.249 1.00 0.00 <br />
ATOM 234 N ASN A 32 -13.784 6.706 -20.227 1.00 0.00 <br />
ATOM 235 CA ASN A 32 -13.610 7.268 -21.563 1.00 0.00 <br />
ATOM 236 C ASN A 32 -13.988 6.222 -22.620 1.00 0.00 <br />
ATOM 237 O ASN A 32 -13.457 6.218 -23.730 1.00 0.00 <br />
ATOM 238 CB ASN A 32 -12.156 7.717 -21.757 1.00 0.00 <br />
ATOM 239 CG ASN A 32 -11.724 8.764 -20.736 1.00 0.00 <br />
ATOM 240 OD1 ASN A 32 -10.536 8.899 -20.437 1.00 0.00 <br />
ATOM 241 ND2 ASN A 32 -12.689 9.514 -20.206 1.00 0.00 <br />
ATOM 242 N GLY A 33 -14.907 5.332 -22.262 1.00 0.00 <br />
ATOM 243 CA GLY A 33 -15.348 4.299 -23.183 1.00 0.00 <br />
ATOM 244 C GLY A 33 -16.858 4.153 -23.140 1.00 0.00 <br />
ATOM 245 O GLY A 33 -17.566 5.050 -22.680 1.00 0.00 <br />
ATOM 246 N LYS A 34 -17.356 3.013 -23.602 1.00 0.00 <br />
ATOM 247 CA LYS A 34 -18.790 2.760 -23.629 1.00 0.00 <br />
ATOM 248 C LYS A 34 -19.330 2.102 -22.363 1.00 0.00 <br />
ATOM 249 O LYS A 34 -18.587 1.494 -21.588 1.00 0.00 <br />
ATOM 250 CB LYS A 34 -19.135 1.859 -24.817 1.00 0.00 <br />
ATOM 251 CG LYS A 34 -18.413 0.520 -24.789 1.00 0.00 <br />
ATOM 252 CD LYS A 34 -19.064 -0.505 -25.711 1.00 0.00 <br />
ATOM 253 CE LYS A 34 -20.442 -0.915 -25.197 1.00 0.00 <br />
ATOM 254 NZ LYS A 34 -21.063 -1.980 -26.035 1.00 0.00 <br />
ATOM 255 N LYS A 35 -20.638 2.228 -22.169 1.00 0.00 <br />
ATOM 256 CA LYS A 35 -21.311 1.609 -21.037 1.00 0.00 <br />
ATOM 257 C LYS A 35 -21.391 0.141 -21.441 1.00 0.00 <br />
ATOM 258 O LYS A 35 -21.684 -0.160 -22.597 1.00 0.00 <br />
ATOM 259 CB LYS A 35 -22.716 2.190 -20.873 1.00 0.00 <br />
ATOM 260 CG LYS A 35 -22.736 3.676 -20.514 1.00 0.00 <br />
ATOM 261 CD LYS A 35 -24.154 4.236 -20.479 1.00 0.00 <br />
ATOM 262 CE LYS A 35 -24.787 4.206 -21.868 1.00 0.00 <br />
ATOM 263 NZ LYS A 35 -26.128 4.854 -21.908 1.00 0.00 <br />
ATOM 264 N PHE A 36 -21.128 -0.769 -20.510 1.00 0.00 <br />
ATOM 265 CA PHE A 36 -21.158 -2.189 -20.842 1.00 0.00 <br />
ATOM 266 C PHE A 36 -22.232 -2.976 -20.104 1.00 0.00 <br />
ATOM 267 O PHE A 36 -22.508 -4.124 -20.445 1.00 0.00 <br />
ATOM 268 CB PHE A 36 -19.777 -2.815 -20.593 1.00 0.00 <br />
ATOM 269 CG PHE A 36 -19.232 -2.572 -19.209 1.00 0.00 <br />
ATOM 270 CD1 PHE A 36 -19.712 -3.287 -18.118 1.00 0.00 <br />
ATOM 271 CD2 PHE A 36 -18.236 -1.618 -18.999 1.00 0.00 <br />
ATOM 272 CE1 PHE A 36 -19.205 -3.056 -16.834 1.00 0.00 <br />
ATOM 273 CE2 PHE A 36 -17.726 -1.380 -17.724 1.00 0.00 <br />
ATOM 274 CZ PHE A 36 -18.213 -2.103 -16.640 1.00 0.00 <br />
ATOM 275 N ASP A 37 -22.847 -2.363 -19.099 1.00 0.00 <br />
ATOM 276 CA ASP A 37 -23.888 -3.052 -18.350 1.00 0.00 <br />
ATOM 277 C ASP A 37 -24.728 -2.064 -17.552 1.00 0.00 <br />
ATOM 278 O ASP A 37 -24.242 -1.013 -17.128 1.00 0.00 <br />
ATOM 279 CB ASP A 37 -23.264 -4.088 -17.408 1.00 0.00 <br />
ATOM 280 CG ASP A 37 -24.275 -5.107 -16.911 1.00 0.00 <br />
ATOM 281 OD1 ASP A 37 -25.448 -5.030 -17.330 1.00 0.00 <br />
ATOM 282 OD2 ASP A 37 -23.902 -5.987 -16.110 1.00 0.00 <br />
ATOM 283 N SER A 38 -25.997 -2.404 -17.358 1.00 0.00 <br />
ATOM 284 CA SER A 38 -26.901 -1.548 -16.603 1.00 0.00 <br />
ATOM 285 C SER A 38 -28.049 -2.351 -16.013 1.00 0.00 <br />
ATOM 286 O SER A 38 -28.886 -2.886 -16.743 1.00 0.00 <br />
ATOM 287 CB SER A 38 -27.462 -0.441 -17.503 1.00 0.00 <br />
ATOM 288 OG SER A 38 -28.493 0.280 -16.846 1.00 0.00 <br />
ATOM 289 N SER A 39 -28.078 -2.442 -14.687 1.00 0.00 <br />
ATOM 290 CA SER A 39 -29.145 -3.159 -14.003 1.00 0.00 <br />
ATOM 291 C SER A 39 -30.408 -2.309 -14.118 1.00 0.00 <br />
ATOM 292 O SER A 39 -31.523 -2.822 -14.055 1.00 0.00 <br />
ATOM 293 CB SER A 39 -28.796 -3.363 -12.525 1.00 0.00 <br />
ATOM 294 OG SER A 39 -28.735 -2.119 -11.842 1.00 0.00 <br />
ATOM 295 N ARG A 40 -30.220 -1.003 -14.289 1.00 0.00 <br />
ATOM 296 CA ARG A 40 -31.340 -0.074 -14.416 1.00 0.00 <br />
ATOM 297 C ARG A 40 -32.046 -0.233 -15.762 1.00 0.00 <br />
ATOM 298 O ARG A 40 -33.268 -0.120 -15.839 1.00 0.00 <br />
ATOM 299 CB ARG A 40 -30.860 1.376 -14.262 1.00 0.00 <br />
ATOM 300 CG ARG A 40 -30.171 1.692 -12.932 1.00 0.00 <br />
ATOM 301 CD ARG A 40 -29.980 3.199 -12.746 1.00 0.00 <br />
ATOM 302 NE ARG A 40 -29.299 3.527 -11.494 1.00 0.00 <br />
ATOM 303 CZ ARG A 40 -27.977 3.548 -11.339 1.00 0.00 <br />
ATOM 304 NH1 ARG A 40 -27.178 3.265 -12.361 1.00 0.00 <br />
ATOM 305 NH2 ARG A 40 -27.449 3.841 -10.153 1.00 0.00 <br />
ATOM 306 N ASP A 41 -31.276 -0.491 -16.818 1.00 0.00 <br />
ATOM 307 CA ASP A 41 -31.847 -0.660 -18.154 1.00 0.00 <br />
ATOM 308 C ASP A 41 -32.739 -1.890 -18.276 1.00 0.00 <br />
ATOM 309 O ASP A 41 -33.630 -1.937 -19.128 1.00 0.00 <br />
ATOM 310 CB ASP A 41 -30.746 -0.731 -19.217 1.00 0.00 <br />
ATOM 311 CG ASP A 41 -30.151 0.634 -19.535 1.00 0.00 <br />
ATOM 312 OD1 ASP A 41 -30.877 1.647 -19.413 1.00 0.00 <br />
ATOM 313 OD2 ASP A 41 -28.964 0.691 -19.925 1.00 0.00 <br />
ATOM 314 N ARG A 42 -32.489 -2.895 -17.444 1.00 0.00 <br />
ATOM 315 CA ARG A 42 -33.302 -4.107 -17.468 1.00 0.00 <br />
ATOM 316 C ARG A 42 -34.241 -4.125 -16.269 1.00 0.00 <br />
ATOM 317 O ARG A 42 -34.891 -5.134 -15.990 1.00 0.00 <br />
ATOM 318 CB ARG A 42 -32.417 -5.356 -17.459 1.00 0.00 <br />
ATOM 319 CG ARG A 42 -31.297 -5.319 -16.444 1.00 0.00 <br />
ATOM 320 CD ARG A 42 -30.666 -6.691 -16.265 1.00 0.00 <br />
ATOM 321 NE ARG A 42 -29.464 -6.621 -15.438 1.00 0.00 <br />
ATOM 322 CZ ARG A 42 -28.287 -6.179 -15.867 1.00 0.00 <br />
ATOM 323 NH1 ARG A 42 -28.146 -5.769 -17.122 1.00 0.00 <br />
ATOM 324 NH2 ARG A 42 -27.250 -6.139 -15.040 1.00 0.00 <br />
ATOM 325 N ASN A 43 -34.319 -2.988 -15.579 1.00 0.00 <br />
ATOM 326 CA ASN A 43 -35.175 -2.829 -14.406 1.00 0.00 <br />
ATOM 327 C ASN A 43 -35.087 -4.044 -13.488 1.00 0.00 <br />
ATOM 328 O ASN A 43 -36.086 -4.718 -13.240 1.00 0.00 <br />
ATOM 329 CB ASN A 43 -36.634 -2.621 -14.832 1.00 0.00 <br />
ATOM 330 CG ASN A 43 -36.826 -1.385 -15.700 1.00 0.00 <br />
ATOM 331 OD1 ASN A 43 -36.462 -1.371 -16.879 1.00 0.00 <br />
ATOM 332 ND2 ASN A 43 -37.400 -0.339 -15.115 1.00 0.00 <br />
ATOM 333 N LYS A 44 -33.893 -4.322 -12.982 1.00 0.00 <br />
ATOM 334 CA LYS A 44 -33.703 -5.468 -12.103 1.00 0.00 <br />
ATOM 335 C LYS A 44 -32.517 -5.268 -11.166 1.00 0.00 <br />
ATOM 336 O LYS A 44 -31.362 -5.377 -11.579 1.00 0.00 <br />
ATOM 337 CB LYS A 44 -33.500 -6.736 -12.942 1.00 0.00 <br />
ATOM 338 CG LYS A 44 -33.408 -8.027 -12.139 1.00 0.00 <br />
ATOM 339 CD LYS A 44 -33.426 -9.243 -13.063 1.00 0.00 <br />
ATOM 340 CE LYS A 44 -33.317 -10.554 -12.291 1.00 0.00 <br />
ATOM 341 NZ LYS A 44 -31.978 -10.744 -11.666 1.00 0.00 <br />
ATOM 342 N PRO A 45 -32.793 -4.960 -9.888 1.00 0.00 <br />
ATOM 343 CA PRO A 45 -31.738 -4.748 -8.893 1.00 0.00 <br />
ATOM 344 C PRO A 45 -30.772 -5.928 -8.838 1.00 0.00 <br />
ATOM 345 O PRO A 45 -31.162 -7.077 -9.061 1.00 0.00 <br />
ATOM 346 CB PRO A 45 -32.522 -4.579 -7.598 1.00 0.00 <br />
ATOM 347 CG PRO A 45 -33.763 -3.883 -8.066 1.00 0.00 <br />
ATOM 348 CD PRO A 45 -34.118 -4.669 -9.310 1.00 0.00 <br />
ATOM 349 N PHE A 46 -29.514 -5.626 -8.539 1.00 0.00 <br />
ATOM 350 CA PHE A 46 -28.450 -6.619 -8.448 1.00 0.00 <br />
ATOM 351 C PHE A 46 -28.140 -6.901 -6.973 1.00 0.00 <br />
ATOM 352 O PHE A 46 -28.031 -5.971 -6.170 1.00 0.00 <br />
ATOM 353 CB PHE A 46 -27.201 -6.068 -9.142 1.00 0.00 <br />
ATOM 354 CG PHE A 46 -26.012 -6.979 -9.083 1.00 0.00 <br />
ATOM 355 CD1 PHE A 46 -25.932 -8.098 -9.908 1.00 0.00 <br />
ATOM 356 CD2 PHE A 46 -24.952 -6.703 -8.220 1.00 0.00 <br />
ATOM 357 CE1 PHE A 46 -24.806 -8.931 -9.877 1.00 0.00 <br />
ATOM 358 CE2 PHE A 46 -23.823 -7.527 -8.179 1.00 0.00 <br />
ATOM 359 CZ PHE A 46 -23.747 -8.641 -9.008 1.00 0.00 <br />
ATOM 360 N LYS A 47 -27.997 -8.174 -6.618 1.00 0.00 <br />
ATOM 361 CA LYS A 47 -27.697 -8.540 -5.235 1.00 0.00 <br />
ATOM 362 C LYS A 47 -26.396 -9.325 -5.123 1.00 0.00 <br />
ATOM 363 O LYS A 47 -26.051 -10.107 -6.012 1.00 0.00 <br />
ATOM 364 CB LYS A 47 -28.832 -9.389 -4.641 1.00 0.00 <br />
ATOM 365 CG LYS A 47 -30.208 -8.726 -4.643 1.00 0.00 <br />
ATOM 366 CD LYS A 47 -31.244 -9.609 -3.937 1.00 0.00 <br />
ATOM 367 CE LYS A 47 -32.640 -9.011 -4.018 1.00 0.00 <br />
ATOM 368 NZ LYS A 47 -33.644 -9.817 -3.269 1.00 0.00 <br />
ATOM 369 N PHE A 48 -25.672 -9.108 -4.031 1.00 0.00 <br />
ATOM 370 CA PHE A 48 -24.429 -9.829 -3.781 1.00 0.00 <br />
ATOM 371 C PHE A 48 -24.117 -9.793 -2.295 1.00 0.00 <br />
ATOM 372 O PHE A 48 -24.493 -8.851 -1.596 1.00 0.00 <br />
ATOM 373 CB PHE A 48 -23.255 -9.237 -4.575 1.00 0.00 <br />
ATOM 374 CG PHE A 48 -22.809 -7.880 -4.098 1.00 0.00 <br />
ATOM 375 CD1 PHE A 48 -23.532 -6.738 -4.423 1.00 0.00 <br />
ATOM 376 CD2 PHE A 48 -21.653 -7.745 -3.334 1.00 0.00 <br />
ATOM 377 CE1 PHE A 48 -23.105 -5.470 -3.995 1.00 0.00 <br />
ATOM 378 CE2 PHE A 48 -21.218 -6.489 -2.900 1.00 0.00 <br />
ATOM 379 CZ PHE A 48 -21.947 -5.350 -3.233 1.00 0.00 <br />
ATOM 380 N ARG A 49 -23.429 -10.829 -1.825 1.00 0.00 <br />
ATOM 381 CA ARG A 49 -23.059 -10.968 -0.418 1.00 0.00 <br />
ATOM 382 C ARG A 49 -21.734 -10.287 -0.090 1.00 0.00 <br />
ATOM 383 O ARG A 49 -20.716 -10.525 -0.748 1.00 0.00 <br />
ATOM 384 CB ARG A 49 -22.951 -12.452 -0.058 1.00 0.00 <br />
ATOM 385 CG ARG A 49 -24.171 -13.286 -0.420 1.00 0.00 <br />
ATOM 386 CD ARG A 49 -23.766 -14.719 -0.764 1.00 0.00 <br />
ATOM 387 NE ARG A 49 -23.007 -15.364 0.306 1.00 0.00 <br />
ATOM 388 CZ ARG A 49 -22.374 -16.527 0.179 1.00 0.00 <br />
ATOM 389 NH1 ARG A 49 -22.404 -17.182 -0.975 1.00 0.00 <br />
ATOM 390 NH2 ARG A 49 -21.708 -17.040 1.206 1.00 0.00 <br />
ATOM 391 N ILE A 50 -21.755 -9.451 0.942 1.00 0.00 <br />
ATOM 392 CA ILE A 50 -20.566 -8.739 1.395 1.00 0.00 <br />
ATOM 393 C ILE A 50 -19.517 -9.697 1.954 1.00 0.00 <br />
ATOM 394 O ILE A 50 -19.832 -10.568 2.758 1.00 0.00 <br />
ATOM 395 CB ILE A 50 -20.925 -7.719 2.508 1.00 0.00 <br />
ATOM 396 CG1 ILE A 50 -21.499 -6.444 1.886 1.00 0.00 <br />
ATOM 397 CG2 ILE A 50 -19.697 -7.414 3.361 1.00 0.00 <br />
ATOM 398 CD1 ILE A 50 -20.498 -5.673 1.043 1.00 0.00 <br />
ATOM 399 N GLY A 51 -18.272 -9.530 1.522 1.00 0.00 <br />
ATOM 400 CA GLY A 51 -17.189 -10.361 2.021 1.00 0.00 <br />
ATOM 401 C GLY A 51 -17.100 -11.785 1.506 1.00 0.00 <br />
ATOM 402 O GLY A 51 -16.335 -12.591 2.044 1.00 0.00 <br />
ATOM 403 N LYS A 52 -17.870 -12.107 0.472 1.00 0.00 <br />
ATOM 404 CA LYS A 52 -17.849 -13.452 -0.086 1.00 0.00 <br />
ATOM 405 C LYS A 52 -17.088 -13.521 -1.405 1.00 0.00 <br />
ATOM 406 O LYS A 52 -17.124 -14.539 -2.097 1.00 0.00 <br />
ATOM 407 CB LYS A 52 -19.277 -13.965 -0.282 1.00 0.00 <br />
ATOM 408 CG LYS A 52 -20.037 -14.182 1.018 1.00 0.00 <br />
ATOM 409 CD LYS A 52 -19.334 -15.209 1.898 1.00 0.00 <br />
ATOM 410 CE LYS A 52 -20.107 -15.474 3.179 1.00 0.00 <br />
ATOM 411 NZ LYS A 52 -19.443 -16.511 4.020 1.00 0.00 <br />
ATOM 412 N GLN A 53 -16.403 -12.435 -1.749 1.00 0.00 <br />
ATOM 413 CA GLN A 53 -15.627 -12.380 -2.984 1.00 0.00 <br />
ATOM 414 C GLN A 53 -16.453 -12.745 -4.212 1.00 0.00 <br />
ATOM 415 O GLN A 53 -15.972 -13.447 -5.103 1.00 0.00 <br />
ATOM 416 CB GLN A 53 -14.432 -13.326 -2.889 1.00 0.00 <br />
ATOM 417 CG GLN A 53 -13.499 -13.013 -1.738 1.00 0.00 <br />
ATOM 418 CD GLN A 53 -12.503 -14.119 -1.491 1.00 0.00 <br />
ATOM 419 OE1 GLN A 53 -12.881 -15.255 -1.200 1.00 0.00 <br />
ATOM 420 NE2 GLN A 53 -11.219 -13.796 -1.602 1.00 0.00 <br />
ATOM 421 N GLU A 54 -17.692 -12.271 -4.268 1.00 0.00 <br />
ATOM 422 CA GLU A 54 -18.543 -12.569 -5.416 1.00 0.00 <br />
ATOM 423 C GLU A 54 -18.362 -11.547 -6.533 1.00 0.00 <br />
ATOM 424 O GLU A 54 -18.608 -11.846 -7.702 1.00 0.00 <br />
ATOM 425 CB GLU A 54 -20.012 -12.595 -4.999 1.00 0.00 <br />
ATOM 426 CG GLU A 54 -20.307 -13.506 -3.826 1.00 0.00 <br />
ATOM 427 CD GLU A 54 -21.785 -13.651 -3.582 1.00 0.00 <br />
ATOM 428 OE1 GLU A 54 -22.499 -12.628 -3.654 1.00 0.00 <br />
ATOM 429 OE2 GLU A 54 -22.232 -14.786 -3.313 1.00 0.00 <br />
ATOM 430 N VAL A 55 -17.933 -10.341 -6.172 1.00 0.00 <br />
ATOM 431 CA VAL A 55 -17.741 -9.276 -7.152 1.00 0.00 <br />
ATOM 432 C VAL A 55 -16.340 -8.677 -7.046 1.00 0.00 <br />
ATOM 433 O VAL A 55 -15.673 -8.827 -6.022 1.00 0.00 <br />
ATOM 434 CB VAL A 55 -18.788 -8.160 -6.951 1.00 0.00 <br />
ATOM 435 CG1 VAL A 55 -20.200 -8.755 -7.006 1.00 0.00 <br />
ATOM 436 CG2 VAL A 55 -18.560 -7.464 -5.613 1.00 0.00 <br />
ATOM 437 N ILE A 56 -15.894 -7.999 -8.100 1.00 0.00 <br />
ATOM 438 CA ILE A 56 -14.564 -7.394 -8.092 1.00 0.00 <br />
ATOM 439 C ILE A 56 -14.374 -6.523 -6.853 1.00 0.00 <br />
ATOM 440 O ILE A 56 -15.321 -5.901 -6.371 1.00 0.00 <br />
ATOM 441 CB ILE A 56 -14.307 -6.554 -9.375 1.00 0.00 <br />
ATOM 442 CG1 ILE A 56 -15.440 -5.551 -9.602 1.00 0.00 <br />
ATOM 443 CG2 ILE A 56 -14.182 -7.488 -10.575 1.00 0.00 <br />
ATOM 444 CD1 ILE A 56 -15.210 -4.630 -10.793 1.00 0.00 <br />
ATOM 445 N LYS A 57 -13.144 -6.485 -6.345 1.00 0.00 <br />
ATOM 446 CA LYS A 57 -12.824 -5.723 -5.138 1.00 0.00 <br />
ATOM 447 C LYS A 57 -13.315 -4.287 -5.109 1.00 0.00 <br />
ATOM 448 O LYS A 57 -13.879 -3.841 -4.111 1.00 0.00 <br />
ATOM 449 CB LYS A 57 -11.313 -5.731 -4.885 1.00 0.00 <br />
ATOM 450 CG LYS A 57 -10.787 -7.039 -4.334 1.00 0.00 <br />
ATOM 451 CD LYS A 57 -9.324 -6.910 -3.923 1.00 0.00 <br />
ATOM 452 CE LYS A 57 -8.825 -8.180 -3.246 1.00 0.00 <br />
ATOM 453 NZ LYS A 57 -7.395 -8.065 -2.826 1.00 0.00 <br />
ATOM 454 N GLY A 58 -13.080 -3.562 -6.199 1.00 0.00 <br />
ATOM 455 CA GLY A 58 -13.492 -2.175 -6.264 1.00 0.00 <br />
ATOM 456 C GLY A 58 -14.979 -1.931 -6.085 1.00 0.00 <br />
ATOM 457 O GLY A 58 -15.385 -0.942 -5.471 1.00 0.00 <br />
ATOM 458 N PHE A 59 -15.797 -2.826 -6.624 1.00 0.00 <br />
ATOM 459 CA PHE A 59 -17.242 -2.687 -6.527 1.00 0.00 <br />
ATOM 460 C PHE A 59 -17.673 -2.948 -5.086 1.00 0.00 <br />
ATOM 461 O PHE A 59 -18.462 -2.191 -4.519 1.00 0.00 <br />
ATOM 462 CB PHE A 59 -17.915 -3.664 -7.498 1.00 0.00 <br />
ATOM 463 CG PHE A 59 -19.390 -3.413 -7.703 1.00 0.00 <br />
ATOM 464 CD1 PHE A 59 -20.328 -3.891 -6.788 1.00 0.00 <br />
ATOM 465 CD2 PHE A 59 -19.840 -2.725 -8.828 1.00 0.00 <br />
ATOM 466 CE1 PHE A 59 -21.693 -3.692 -6.990 1.00 0.00 <br />
ATOM 467 CE2 PHE A 59 -21.204 -2.517 -9.044 1.00 0.00 <br />
ATOM 468 CZ PHE A 59 -22.136 -3.003 -8.123 1.00 0.00 <br />
ATOM 469 N GLU A 60 -17.132 -4.001 -4.482 1.00 0.00 <br />
ATOM 470 CA GLU A 60 -17.483 -4.323 -3.105 1.00 0.00 <br />
ATOM 471 C GLU A 60 -16.952 -3.283 -2.119 1.00 0.00 <br />
ATOM 472 O GLU A 60 -17.652 -2.894 -1.191 1.00 0.00 <br />
ATOM 473 CB GLU A 60 -16.958 -5.706 -2.707 1.00 0.00 <br />
ATOM 474 CG GLU A 60 -17.614 -6.211 -1.425 1.00 0.00 <br />
ATOM 475 CD GLU A 60 -17.145 -7.584 -1.006 1.00 0.00 <br />
ATOM 476 OE1 GLU A 60 -16.906 -8.432 -1.892 1.00 0.00 <br />
ATOM 477 OE2 GLU A 60 -17.035 -7.820 0.218 1.00 0.00 <br />
ATOM 478 N GLU A 61 -15.713 -2.837 -2.311 1.00 0.00 <br />
ATOM 479 CA GLU A 61 -15.147 -1.839 -1.410 1.00 0.00 <br />
ATOM 480 C GLU A 61 -15.923 -0.531 -1.516 1.00 0.00 <br />
ATOM 481 O GLU A 61 -16.061 0.204 -0.537 1.00 0.00 <br />
ATOM 482 CB GLU A 61 -13.669 -1.603 -1.728 1.00 0.00 <br />
ATOM 483 CG GLU A 61 -12.814 -2.848 -1.570 1.00 0.00 <br />
ATOM 484 CD GLU A 61 -11.345 -2.583 -1.813 1.00 0.00 <br />
ATOM 485 OE1 GLU A 61 -11.027 -1.644 -2.575 1.00 0.00 <br />
ATOM 486 OE2 GLU A 61 -10.510 -3.324 -1.255 1.00 0.00 <br />
ATOM 487 N GLY A 62 -16.429 -0.240 -2.709 1.00 0.00 <br />
ATOM 488 CA GLY A 62 -17.199 0.974 -2.888 1.00 0.00 <br />
ATOM 489 C GLY A 62 -18.501 0.877 -2.109 1.00 0.00 <br />
ATOM 490 O GLY A 62 -18.852 1.769 -1.333 1.00 0.00 <br />
ATOM 491 N ALA A 63 -19.212 -0.228 -2.306 1.00 0.00 <br />
ATOM 492 CA ALA A 63 -20.487 -0.447 -1.635 1.00 0.00 <br />
ATOM 493 C ALA A 63 -20.334 -0.496 -0.123 1.00 0.00 <br />
ATOM 494 O ALA A 63 -21.180 0.016 0.615 1.00 0.00 <br />
ATOM 495 CB ALA A 63 -21.115 -1.742 -2.131 1.00 0.00 <br />
ATOM 496 N ALA A 64 -19.252 -1.118 0.337 1.00 0.00 <br />
ATOM 497 CA ALA A 64 -19.001 -1.252 1.764 1.00 0.00 <br />
ATOM 498 C ALA A 64 -18.902 0.092 2.481 1.00 0.00 <br />
ATOM 499 O ALA A 64 -19.242 0.190 3.661 1.00 0.00 <br />
ATOM 500 CB ALA A 64 -17.731 -2.069 1.996 1.00 0.00 <br />
ATOM 501 N GLN A 65 -18.452 1.129 1.779 1.00 0.00 <br />
ATOM 502 CA GLN A 65 -18.321 2.444 2.408 1.00 0.00 <br />
ATOM 503 C GLN A 65 -19.489 3.386 2.132 1.00 0.00 <br />
ATOM 504 O GLN A 65 -19.404 4.588 2.396 1.00 0.00 <br />
ATOM 505 CB GLN A 65 -17.011 3.111 1.981 1.00 0.00 <br />
ATOM 506 CG GLN A 65 -16.896 3.386 0.498 1.00 0.00 <br />
ATOM 507 CD GLN A 65 -15.542 3.956 0.135 1.00 0.00 <br />
ATOM 508 OE1 GLN A 65 -15.246 5.122 0.416 1.00 0.00 <br />
ATOM 509 NE2 GLN A 65 -14.705 3.135 -0.473 1.00 0.00 <br />
ATOM 510 N MET A 66 -20.574 2.837 1.599 1.00 0.00 <br />
ATOM 511 CA MET A 66 -21.769 3.621 1.297 1.00 0.00 <br />
ATOM 512 C MET A 66 -22.858 3.312 2.322 1.00 0.00 <br />
ATOM 513 O MET A 66 -22.951 2.186 2.809 1.00 0.00 <br />
ATOM 514 CB MET A 66 -22.278 3.286 -0.107 1.00 0.00 <br />
ATOM 515 CG MET A 66 -21.360 3.779 -1.227 1.00 0.00 <br />
ATOM 516 SD MET A 66 -21.802 3.102 -2.840 1.00 0.00 <br />
ATOM 517 CE MET A 66 -23.385 3.919 -3.121 1.00 0.00 <br />
ATOM 518 N SER A 67 -23.673 4.307 2.655 1.00 0.00 <br />
ATOM 519 CA SER A 67 -24.753 4.094 3.613 1.00 0.00 <br />
ATOM 520 C SER A 67 -26.065 3.852 2.864 1.00 0.00 <br />
ATOM 521 O SER A 67 -26.175 4.150 1.668 1.00 0.00 <br />
ATOM 522 CB SER A 67 -24.879 5.289 4.574 1.00 0.00 <br />
ATOM 523 OG SER A 67 -25.060 6.519 3.893 1.00 0.00 <br />
ATOM 524 N LEU A 68 -27.052 3.300 3.565 1.00 0.00 <br />
ATOM 525 CA LEU A 68 -28.343 2.990 2.959 1.00 0.00 <br />
ATOM 526 C LEU A 68 -28.934 4.161 2.183 1.00 0.00 <br />
ATOM 527 O LEU A 68 -29.022 5.274 2.697 1.00 0.00 <br />
ATOM 528 CB LEU A 68 -29.337 2.534 4.033 1.00 0.00 <br />
ATOM 529 CG LEU A 68 -30.677 2.004 3.514 1.00 0.00 <br />
ATOM 530 CD1 LEU A 68 -30.438 0.840 2.560 1.00 0.00 <br />
ATOM 531 CD2 LEU A 68 -31.539 1.556 4.689 1.00 0.00 <br />
ATOM 532 N GLY A 69 -29.331 3.896 0.940 1.00 0.00 <br />
ATOM 533 CA GLY A 69 -29.915 4.928 0.094 1.00 0.00 <br />
ATOM 534 C GLY A 69 -28.910 5.768 -0.678 1.00 0.00 <br />
ATOM 535 O GLY A 69 -29.282 6.535 -1.569 1.00 0.00 <br />
ATOM 536 N GLN A 70 -27.629 5.632 -0.348 1.00 0.00 <br />
ATOM 537 CA GLN A 70 -26.611 6.413 -1.033 1.00 0.00 <br />
ATOM 538 C GLN A 70 -26.414 5.947 -2.464 1.00 0.00 <br />
ATOM 539 O GLN A 70 -26.568 4.764 -2.770 1.00 0.00 <br />
ATOM 540 CB GLN A 70 -25.268 6.322 -0.299 1.00 0.00 <br />
ATOM 541 CG GLN A 70 -24.212 7.269 -0.843 1.00 0.00 <br />
ATOM 542 CD GLN A 70 -22.892 7.173 -0.083 1.00 0.00 <br />
ATOM 543 OE1 GLN A 70 -22.825 6.580 0.993 1.00 0.00 <br />
ATOM 544 NE2 GLN A 70 -21.841 7.771 -0.640 1.00 0.00 <br />
ATOM 545 N ARG A 71 -26.081 6.899 -3.334 1.00 0.00 <br />
ATOM 546 CA ARG A 71 -25.802 6.632 -4.739 1.00 0.00 <br />
ATOM 547 C ARG A 71 -24.497 7.348 -5.030 1.00 0.00 <br />
ATOM 548 O ARG A 71 -24.319 8.513 -4.659 1.00 0.00 <br />
ATOM 549 CB ARG A 71 -26.902 7.190 -5.646 1.00 0.00 <br />
ATOM 550 CG ARG A 71 -26.590 7.038 -7.127 1.00 0.00 <br />
ATOM 551 CD ARG A 71 -27.729 7.569 -7.984 1.00 0.00 <br />
ATOM 552 NE ARG A 71 -27.481 7.406 -9.413 1.00 0.00 <br />
ATOM 553 CZ ARG A 71 -28.266 7.914 -10.361 1.00 0.00 <br />
ATOM 554 NH1 ARG A 71 -29.343 8.617 -10.021 1.00 0.00 <br />
ATOM 555 NH2 ARG A 71 -27.983 7.719 -11.644 1.00 0.00 <br />
ATOM 556 N ALA A 72 -23.575 6.664 -5.692 1.00 0.00 <br />
ATOM 557 CA ALA A 72 -22.300 7.284 -5.968 1.00 0.00 <br />
ATOM 558 C ALA A 72 -21.643 6.762 -7.226 1.00 0.00 <br />
ATOM 559 O ALA A 72 -21.975 5.689 -7.726 1.00 0.00 <br />
ATOM 560 CB ALA A 72 -21.367 7.083 -4.781 1.00 0.00 <br />
ATOM 561 N LYS A 73 -20.706 7.552 -7.728 1.00 0.00 <br />
ATOM 562 CA LYS A 73 -19.935 7.202 -8.907 1.00 0.00 <br />
ATOM 563 C LYS A 73 -18.658 6.549 -8.385 1.00 0.00 <br />
ATOM 564 O LYS A 73 -17.917 7.162 -7.608 1.00 0.00 <br />
ATOM 565 CB LYS A 73 -19.588 8.471 -9.689 1.00 0.00 <br />
ATOM 566 CG LYS A 73 -18.573 8.289 -10.805 1.00 0.00 <br />
ATOM 567 CD LYS A 73 -18.169 9.649 -11.368 1.00 0.00 <br />
ATOM 568 CE LYS A 73 -17.260 9.522 -12.575 1.00 0.00 <br />
ATOM 569 NZ LYS A 73 -16.030 8.757 -12.253 1.00 0.00 <br />
ATOM 570 N LEU A 74 -18.405 5.303 -8.780 1.00 0.00 <br />
ATOM 571 CA LEU A 74 -17.196 4.628 -8.326 1.00 0.00 <br />
ATOM 572 C LEU A 74 -16.200 4.546 -9.470 1.00 0.00 <br />
ATOM 573 O LEU A 74 -16.546 4.130 -10.578 1.00 0.00 <br />
ATOM 574 CB LEU A 74 -17.487 3.201 -7.844 1.00 0.00 <br />
ATOM 575 CG LEU A 74 -18.759 2.834 -7.078 1.00 0.00 <br />
ATOM 576 CD1 LEU A 74 -18.576 1.442 -6.495 1.00 0.00 <br />
ATOM 577 CD2 LEU A 74 -19.045 3.828 -5.981 1.00 0.00 <br />
ATOM 578 N THR A 75 -14.967 4.958 -9.209 1.00 0.00 <br />
ATOM 579 CA THR A 75 -13.935 4.865 -10.222 1.00 0.00 <br />
ATOM 580 C THR A 75 -12.982 3.799 -9.704 1.00 0.00 <br />
ATOM 581 O THR A 75 -12.352 3.969 -8.658 1.00 0.00 <br />
ATOM 582 CB THR A 75 -13.196 6.197 -10.409 1.00 0.00 <br />
ATOM 583 OG1 THR A 75 -14.144 7.221 -10.746 1.00 0.00 <br />
ATOM 584 CG2 THR A 75 -12.171 6.078 -11.536 1.00 0.00 <br />
ATOM 585 N CYS A 76 -12.897 2.695 -10.437 1.00 0.00 <br />
ATOM 586 CA CYS A 76 -12.063 1.569 -10.044 1.00 0.00 <br />
ATOM 587 C CYS A 76 -10.873 1.349 -10.972 1.00 0.00 <br />
ATOM 588 O CYS A 76 -11.045 1.139 -12.174 1.00 0.00 <br />
ATOM 589 CB CYS A 76 -12.909 0.292 -10.016 1.00 0.00 <br />
ATOM 590 SG CYS A 76 -14.468 0.417 -9.079 1.00 0.00 <br />
ATOM 591 N THR A 77 -9.669 1.395 -10.411 1.00 0.00 <br />
ATOM 592 CA THR A 77 -8.467 1.159 -11.203 1.00 0.00 <br />
ATOM 593 C THR A 77 -8.425 -0.340 -11.518 1.00 0.00 <br />
ATOM 594 O THR A 77 -9.075 -1.147 -10.845 1.00 0.00 <br />
ATOM 595 CB THR A 77 -7.188 1.575 -10.434 1.00 0.00 <br />
ATOM 596 OG1 THR A 77 -7.215 1.014 -9.116 1.00 0.00 <br />
ATOM 597 CG2 THR A 77 -7.096 3.094 -10.336 1.00 0.00 <br />
ATOM 598 N PRO A 78 -7.664 -0.731 -12.551 1.00 0.00 <br />
ATOM 599 CA PRO A 78 -7.550 -2.137 -12.953 1.00 0.00 <br />
ATOM 600 C PRO A 78 -7.252 -3.129 -11.823 1.00 0.00 <br />
ATOM 601 O PRO A 78 -7.852 -4.205 -11.765 1.00 0.00 <br />
ATOM 602 CB PRO A 78 -6.432 -2.110 -13.995 1.00 0.00 <br />
ATOM 603 CG PRO A 78 -6.552 -0.742 -14.588 1.00 0.00 <br />
ATOM 604 CD PRO A 78 -6.785 0.122 -13.373 1.00 0.00 <br />
ATOM 605 N ASP A 79 -6.335 -2.771 -10.926 1.00 0.00 <br />
ATOM 606 CA ASP A 79 -5.965 -3.672 -9.836 1.00 0.00 <br />
ATOM 607 C ASP A 79 -7.124 -4.062 -8.914 1.00 0.00 <br />
ATOM 608 O ASP A 79 -7.050 -5.081 -8.227 1.00 0.00 <br />
ATOM 609 CB ASP A 79 -4.814 -3.077 -9.015 1.00 0.00 <br />
ATOM 610 CG ASP A 79 -5.149 -1.726 -8.445 1.00 0.00 <br />
ATOM 611 OD1 ASP A 79 -5.459 -0.813 -9.233 1.00 0.00 <br />
ATOM 612 OD2 ASP A 79 -5.101 -1.574 -7.212 1.00 0.00 <br />
ATOM 613 N VAL A 80 -8.183 -3.254 -8.885 1.00 0.00 <br />
ATOM 614 CA VAL A 80 -9.349 -3.580 -8.067 1.00 0.00 <br />
ATOM 615 C VAL A 80 -10.546 -3.901 -8.971 1.00 0.00 <br />
ATOM 616 O VAL A 80 -11.698 -3.845 -8.544 1.00 0.00 <br />
ATOM 617 CB VAL A 80 -9.716 -2.432 -7.082 1.00 0.00 <br />
ATOM 618 CG1 VAL A 80 -8.655 -2.336 -5.979 1.00 0.00 <br />
ATOM 619 CG2 VAL A 80 -9.832 -1.108 -7.826 1.00 0.00 <br />
ATOM 620 N ALA A 81 -10.252 -4.235 -10.227 1.00 0.00 <br />
ATOM 621 CA ALA A 81 -11.277 -4.602 -11.196 1.00 0.00 <br />
ATOM 622 C ALA A 81 -10.854 -5.906 -11.884 1.00 0.00 <br />
ATOM 623 O ALA A 81 -10.777 -6.951 -11.233 1.00 0.00 <br />
ATOM 624 CB ALA A 81 -11.466 -3.486 -12.227 1.00 0.00 <br />
ATOM 625 N TYR A 82 -10.555 -5.848 -13.180 1.00 0.00 <br />
ATOM 626 CA TYR A 82 -10.157 -7.049 -13.914 1.00 0.00 <br />
ATOM 627 C TYR A 82 -8.664 -7.146 -14.248 1.00 0.00 <br />
ATOM 628 O TYR A 82 -8.232 -8.062 -14.952 1.00 0.00 <br />
ATOM 629 CB TYR A 82 -11.020 -7.178 -15.178 1.00 0.00 <br />
ATOM 630 CG TYR A 82 -12.484 -7.397 -14.844 1.00 0.00 <br />
ATOM 631 CD1 TYR A 82 -12.947 -8.650 -14.432 1.00 0.00 <br />
ATOM 632 CD2 TYR A 82 -13.393 -6.338 -14.870 1.00 0.00 <br />
ATOM 633 CE1 TYR A 82 -14.280 -8.841 -14.046 1.00 0.00 <br />
ATOM 634 CE2 TYR A 82 -14.730 -6.518 -14.490 1.00 0.00 <br />
ATOM 635 CZ TYR A 82 -15.162 -7.770 -14.076 1.00 0.00 <br />
ATOM 636 OH TYR A 82 -16.466 -7.938 -13.668 1.00 0.00 <br />
ATOM 637 N GLY A 83 -7.885 -6.198 -13.739 1.00 0.00 <br />
ATOM 638 CA GLY A 83 -6.445 -6.208 -13.944 1.00 0.00 <br />
ATOM 639 C GLY A 83 -5.895 -6.301 -15.357 1.00 0.00 <br />
ATOM 640 O GLY A 83 -6.486 -5.792 -16.307 1.00 0.00 <br />
ATOM 641 N ALA A 84 -4.746 -6.959 -15.486 1.00 0.00 <br />
ATOM 642 CA ALA A 84 -4.080 -7.109 -16.776 1.00 0.00 <br />
ATOM 643 C ALA A 84 -4.792 -8.114 -17.665 1.00 0.00 <br />
ATOM 644 O ALA A 84 -4.618 -8.108 -18.883 1.00 0.00 <br />
ATOM 645 CB ALA A 84 -2.636 -7.538 -16.568 1.00 0.00 <br />
ATOM 646 N THR A 85 -5.596 -8.971 -17.048 1.00 0.00 <br />
ATOM 647 CA THR A 85 -6.330 -9.998 -17.776 1.00 0.00 <br />
ATOM 648 C THR A 85 -7.594 -9.470 -18.440 1.00 0.00 <br />
ATOM 649 O THR A 85 -7.944 -9.903 -19.538 1.00 0.00 <br />
ATOM 650 CB THR A 85 -6.745 -11.156 -16.843 1.00 0.00 <br />
ATOM 651 OG1 THR A 85 -5.584 -11.705 -16.214 1.00 0.00 <br />
ATOM 652 CG2 THR A 85 -7.459 -12.252 -17.633 1.00 0.00 <br />
ATOM 653 N GLY A 86 -8.275 -8.542 -17.771 1.00 0.00 <br />
ATOM 654 CA GLY A 86 -9.514 -8.003 -18.301 1.00 0.00 <br />
ATOM 655 C GLY A 86 -10.593 -9.071 -18.186 1.00 0.00 <br />
ATOM 656 O GLY A 86 -10.348 -10.127 -17.610 1.00 0.00 <br />
ATOM 657 N HIS A 87 -11.787 -8.796 -18.704 1.00 0.00 <br />
ATOM 658 CA HIS A 87 -12.871 -9.776 -18.677 1.00 0.00 <br />
ATOM 659 C HIS A 87 -13.148 -10.182 -20.125 1.00 0.00 <br />
ATOM 660 O HIS A 87 -13.560 -9.354 -20.939 1.00 0.00 <br />
ATOM 661 CB HIS A 87 -14.139 -9.181 -18.057 1.00 0.00 <br />
ATOM 662 CG HIS A 87 -15.283 -10.143 -18.001 1.00 0.00 <br />
ATOM 663 ND1 HIS A 87 -15.322 -11.202 -17.118 1.00 0.00 <br />
ATOM 664 CD2 HIS A 87 -16.407 -10.233 -18.748 1.00 0.00 <br />
ATOM 665 CE1 HIS A 87 -16.424 -11.903 -17.324 1.00 0.00 <br />
ATOM 666 NE2 HIS A 87 -17.100 -11.337 -18.309 1.00 0.00 <br />
ATOM 667 N PRO A 88 -12.927 -11.464 -20.460 1.00 0.00 <br />
ATOM 668 CA PRO A 88 -13.140 -11.985 -21.813 1.00 0.00 <br />
ATOM 669 C PRO A 88 -14.260 -11.359 -22.632 1.00 0.00 <br />
ATOM 670 O PRO A 88 -15.435 -11.455 -22.277 1.00 0.00 <br />
ATOM 671 CB PRO A 88 -13.354 -13.476 -21.570 1.00 0.00 <br />
ATOM 672 CG PRO A 88 -12.350 -13.741 -20.477 1.00 0.00 <br />
ATOM 673 CD PRO A 88 -12.577 -12.558 -19.532 1.00 0.00 <br />
ATOM 674 N GLY A 89 -13.870 -10.708 -23.726 1.00 0.00 <br />
ATOM 675 CA GLY A 89 -14.820 -10.091 -24.638 1.00 0.00 <br />
ATOM 676 C GLY A 89 -15.633 -8.892 -24.181 1.00 0.00 <br />
ATOM 677 O GLY A 89 -16.491 -8.427 -24.926 1.00 0.00 <br />
ATOM 678 N VAL A 90 -15.378 -8.376 -22.982 1.00 0.00 <br />
ATOM 679 CA VAL A 90 -16.140 -7.228 -22.492 1.00 0.00 <br />
ATOM 680 C VAL A 90 -15.254 -6.116 -21.923 1.00 0.00 <br />
ATOM 681 O VAL A 90 -15.404 -4.945 -22.280 1.00 0.00 <br />
ATOM 682 CB VAL A 90 -17.147 -7.655 -21.395 1.00 0.00 <br />
ATOM 683 CG1 VAL A 90 -18.042 -6.484 -21.030 1.00 0.00 <br />
ATOM 684 CG2 VAL A 90 -17.979 -8.835 -21.881 1.00 0.00 <br />
ATOM 685 N ILE A 91 -14.338 -6.491 -21.034 1.00 0.00 <br />
ATOM 686 CA ILE A 91 -13.427 -5.533 -20.408 1.00 0.00 <br />
ATOM 687 C ILE A 91 -11.994 -5.844 -20.841 1.00 0.00 <br />
ATOM 688 O ILE A 91 -11.483 -6.937 -20.583 1.00 0.00 <br />
ATOM 689 CB ILE A 91 -13.467 -5.634 -18.864 1.00 0.00 <br />
ATOM 690 CG1 ILE A 91 -14.913 -5.540 -18.355 1.00 0.00 <br />
ATOM 691 CG2 ILE A 91 -12.562 -4.552 -18.250 1.00 0.00 <br />
ATOM 692 CD1 ILE A 91 -15.621 -4.225 -18.679 1.00 0.00 <br />
ATOM 693 N PRO A 92 -11.321 -4.886 -21.501 1.00 0.00 <br />
ATOM 694 CA PRO A 92 -9.941 -5.129 -21.936 1.00 0.00 <br />
ATOM 695 C PRO A 92 -8.929 -5.029 -20.802 1.00 0.00 <br />
ATOM 696 O PRO A 92 -9.249 -4.561 -19.706 1.00 0.00 <br />
ATOM 697 CB PRO A 92 -9.716 -4.042 -22.985 1.00 0.00 <br />
ATOM 698 CG PRO A 92 -10.539 -2.910 -22.458 1.00 0.00 <br />
ATOM 699 CD PRO A 92 -11.822 -3.607 -22.031 1.00 0.00 <br />
ATOM 700 N PRO A 93 -7.691 -5.487 -21.050 1.00 0.00 <br />
ATOM 701 CA PRO A 93 -6.636 -5.431 -20.038 1.00 0.00 <br />
ATOM 702 C PRO A 93 -6.411 -3.987 -19.571 1.00 0.00 <br />
ATOM 703 O PRO A 93 -6.597 -3.040 -20.345 1.00 0.00 <br />
ATOM 704 CB PRO A 93 -5.426 -5.984 -20.780 1.00 0.00 <br />
ATOM 705 CG PRO A 93 -6.045 -7.000 -21.701 1.00 0.00 <br />
ATOM 706 CD PRO A 93 -7.251 -6.261 -22.228 1.00 0.00 <br />
ATOM 707 N ASN A 94 -6.030 -3.837 -18.304 1.00 0.00 <br />
ATOM 708 CA ASN A 94 -5.740 -2.536 -17.692 1.00 0.00 <br />
ATOM 709 C ASN A 94 -6.852 -1.503 -17.804 1.00 0.00 <br />
ATOM 710 O ASN A 94 -6.586 -0.313 -17.988 1.00 0.00 <br />
ATOM 711 CB ASN A 94 -4.470 -1.934 -18.295 1.00 0.00 <br />
ATOM 712 CG ASN A 94 -3.777 -0.985 -17.335 1.00 0.00 <br />
ATOM 713 OD1 ASN A 94 -3.383 -1.387 -16.244 1.00 0.00 <br />
ATOM 714 ND2 ASN A 94 -3.630 0.271 -17.730 1.00 0.00 <br />
ATOM 715 N ALA A 95 -8.093 -1.941 -17.669 1.00 0.00 <br />
ATOM 716 CA ALA A 95 -9.198 -1.012 -17.786 1.00 0.00 <br />
ATOM 717 C ALA A 95 -9.671 -0.422 -16.469 1.00 0.00 <br />
ATOM 718 O ALA A 95 -9.956 -1.148 -15.512 1.00 0.00 <br />
ATOM 719 CB ALA A 95 -10.369 -1.684 -18.494 1.00 0.00 <br />
ATOM 720 N THR A 96 -9.736 0.904 -16.423 1.00 0.00 <br />
ATOM 721 CA THR A 96 -10.260 1.593 -15.252 1.00 0.00 <br />
ATOM 722 C THR A 96 -11.769 1.614 -15.502 1.00 0.00 <br />
ATOM 723 O THR A 96 -12.228 1.995 -16.589 1.00 0.00 <br />
ATOM 724 CB THR A 96 -9.700 3.031 -15.148 1.00 0.00 <br />
ATOM 725 OG1 THR A 96 -8.320 2.970 -14.751 1.00 0.00 <br />
ATOM 726 CG2 THR A 96 -10.492 3.849 -14.140 1.00 0.00 <br />
ATOM 727 N LEU A 97 -12.543 1.190 -14.510 1.00 0.00 <br />
ATOM 728 CA LEU A 97 -13.992 1.121 -14.674 1.00 0.00 <br />
ATOM 729 C LEU A 97 -14.761 2.144 -13.861 1.00 0.00 <br />
ATOM 730 O LEU A 97 -14.368 2.492 -12.747 1.00 0.00 <br />
ATOM 731 CB LEU A 97 -14.474 -0.283 -14.303 1.00 0.00 <br />
ATOM 732 CG LEU A 97 -13.732 -1.432 -14.998 1.00 0.00 <br />
ATOM 733 CD1 LEU A 97 -14.256 -2.769 -14.495 1.00 0.00 <br />
ATOM 734 CD2 LEU A 97 -13.910 -1.313 -16.508 1.00 0.00 <br />
ATOM 735 N ILE A 98 -15.865 2.618 -14.428 1.00 0.00 <br />
ATOM 736 CA ILE A 98 -16.720 3.582 -13.753 1.00 0.00 <br />
ATOM 737 C ILE A 98 -18.046 2.901 -13.478 1.00 0.00 <br />
ATOM 738 O ILE A 98 -18.666 2.370 -14.400 1.00 0.00 <br />
ATOM 739 CB ILE A 98 -17.013 4.822 -14.628 1.00 0.00 <br />
ATOM 740 CG1 ILE A 98 -15.711 5.516 -15.032 1.00 0.00 <br />
ATOM 741 CG2 ILE A 98 -17.929 5.777 -13.861 1.00 0.00 <br />
ATOM 742 CD1 ILE A 98 -14.936 6.099 -13.871 1.00 0.00 <br />
ATOM 743 N PHE A 99 -18.476 2.921 -12.217 1.00 0.00 <br />
ATOM 744 CA PHE A 99 -19.741 2.310 -11.814 1.00 0.00 <br />
ATOM 745 C PHE A 99 -20.619 3.308 -11.065 1.00 0.00 <br />
ATOM 746 O PHE A 99 -20.193 3.871 -10.056 1.00 0.00 <br />
ATOM 747 CB PHE A 99 -19.500 1.114 -10.882 1.00 0.00 <br />
ATOM 748 CG PHE A 99 -19.076 -0.153 -11.583 1.00 0.00 <br />
ATOM 749 CD1 PHE A 99 -20.014 -0.953 -12.233 1.00 0.00 <br />
ATOM 750 CD2 PHE A 99 -17.749 -0.566 -11.554 1.00 0.00 <br />
ATOM 751 CE1 PHE A 99 -19.630 -2.152 -12.841 1.00 0.00 <br />
ATOM 752 CE2 PHE A 99 -17.354 -1.757 -12.157 1.00 0.00 <br />
ATOM 753 CZ PHE A 99 -18.295 -2.554 -12.801 1.00 0.00 <br />
ATOM 754 N ASP A 100 -21.832 3.531 -11.567 1.00 0.00 <br />
ATOM 755 CA ASP A 100 -22.802 4.417 -10.919 1.00 0.00 <br />
ATOM 756 C ASP A 100 -23.593 3.425 -10.072 1.00 0.00 <br />
ATOM 757 O ASP A 100 -24.371 2.636 -10.609 1.00 0.00 <br />
ATOM 758 CB ASP A 100 -23.724 5.061 -11.962 1.00 0.00 <br />
ATOM 759 CG ASP A 100 -24.763 5.989 -11.343 1.00 0.00 <br />
ATOM 760 OD1 ASP A 100 -25.159 5.770 -10.176 1.00 0.00 <br />
ATOM 761 OD2 ASP A 100 -25.198 6.931 -12.040 1.00 0.00 <br />
ATOM 762 N VAL A 101 -23.385 3.462 -8.761 1.00 0.00 <br />
ATOM 763 CA VAL A 101 -24.031 2.520 -7.849 1.00 0.00 <br />
ATOM 764 C VAL A 101 -24.972 3.155 -6.828 1.00 0.00 <br />
ATOM 765 O VAL A 101 -24.646 4.181 -6.223 1.00 0.00 <br />
ATOM 766 CB VAL A 101 -22.950 1.715 -7.068 1.00 0.00 <br />
ATOM 767 CG1 VAL A 101 -23.601 0.831 -6.002 1.00 0.00 <br />
ATOM 768 CG2 VAL A 101 -22.130 0.866 -8.039 1.00 0.00 <br />
ATOM 769 N GLU A 102 -26.132 2.535 -6.635 1.00 0.00 <br />
ATOM 770 CA GLU A 102 -27.102 3.019 -5.652 1.00 0.00 <br />
ATOM 771 C GLU A 102 -27.435 1.886 -4.674 1.00 0.00 <br />
ATOM 772 O GLU A 102 -27.954 0.845 -5.079 1.00 0.00 <br />
ATOM 773 CB GLU A 102 -28.390 3.503 -6.335 1.00 0.00 <br />
ATOM 774 CG GLU A 102 -29.434 3.975 -5.324 1.00 0.00 <br />
ATOM 775 CD GLU A 102 -30.725 4.468 -5.956 1.00 0.00 <br />
ATOM 776 OE1 GLU A 102 -30.943 4.228 -7.167 1.00 0.00 <br />
ATOM 777 OE2 GLU A 102 -31.531 5.086 -5.224 1.00 0.00 <br />
ATOM 778 N LEU A 103 -27.117 2.088 -3.392 1.00 0.00 <br />
ATOM 779 CA LEU A 103 -27.380 1.085 -2.366 1.00 0.00 <br />
ATOM 780 C LEU A 103 -28.842 1.202 -1.953 1.00 0.00 <br />
ATOM 781 O LEU A 103 -29.199 2.007 -1.094 1.00 0.00 <br />
ATOM 782 CB LEU A 103 -26.468 1.305 -1.156 1.00 0.00 <br />
ATOM 783 CG LEU A 103 -26.609 0.303 -0.005 1.00 0.00 <br />
ATOM 784 CD1 LEU A 103 -26.382 -1.118 -0.505 1.00 0.00 <br />
ATOM 785 CD2 LEU A 103 -25.609 0.653 1.081 1.00 0.00 <br />
ATOM 786 N LEU A 104 -29.675 0.377 -2.570 1.00 0.00 <br />
ATOM 787 CA LEU A 104 -31.111 0.393 -2.332 1.00 0.00 <br />
ATOM 788 C LEU A 104 -31.576 -0.236 -1.027 1.00 0.00 <br />
ATOM 789 O LEU A 104 -32.426 0.320 -0.330 1.00 0.00 <br />
ATOM 790 CB LEU A 104 -31.816 -0.302 -3.490 1.00 0.00 <br />
ATOM 791 CG LEU A 104 -31.473 0.249 -4.875 1.00 0.00 <br />
ATOM 792 CD1 LEU A 104 -31.942 -0.729 -5.949 1.00 0.00 <br />
ATOM 793 CD2 LEU A 104 -32.120 1.615 -5.046 1.00 0.00 <br />
ATOM 794 N ASN A 105 -31.021 -1.393 -0.691 1.00 0.00 <br />
ATOM 795 CA ASN A 105 -31.449 -2.075 0.517 1.00 0.00 <br />
ATOM 796 C ASN A 105 -30.377 -3.035 1.005 1.00 0.00 <br />
ATOM 797 O ASN A 105 -29.434 -3.353 0.276 1.00 0.00 <br />
ATOM 798 CB ASN A 105 -32.746 -2.835 0.206 1.00 0.00 <br />
ATOM 799 CG ASN A 105 -33.449 -3.342 1.448 1.00 0.00 <br />
ATOM 800 OD1 ASN A 105 -33.342 -2.754 2.523 1.00 0.00 <br />
ATOM 801 ND2 ASN A 105 -34.195 -4.431 1.298 1.00 0.00 <br />
ATOM 802 N LEU A 106 -30.524 -3.481 2.248 1.00 0.00 <br />
ATOM 803 CA LEU A 106 -29.600 -4.429 2.856 1.00 0.00 <br />
ATOM 804 C LEU A 106 -30.427 -5.586 3.404 1.00 0.00 <br />
ATOM 805 O LEU A 106 -31.322 -5.377 4.224 1.00 0.00 <br />
ATOM 806 CB LEU A 106 -28.812 -3.754 3.981 1.00 0.00 <br />
ATOM 807 CG LEU A 106 -27.682 -2.843 3.494 1.00 0.00 <br />
ATOM 808 CD1 LEU A 106 -27.164 -1.983 4.632 1.00 0.00 <br />
ATOM 809 CD2 LEU A 106 -26.563 -3.714 2.914 1.00 0.00 <br />
ATOM 810 N GLU A 107 -30.132 -6.800 2.946 1.00 0.00 <br />
ATOM 811 CA GLU A 107 -30.875 -7.980 3.382 1.00 0.00 <br />
ATOM 812 C GLU A 107 -29.979 -9.012 4.061 1.00 0.00 <br />
ATOM 813 O GLU A 107 -28.799 -8.767 4.306 1.00 0.00 <br />
ATOM 814 CB GLU A 107 -31.571 -8.626 2.183 1.00 0.00 <br />
ATOM 815 CG GLU A 107 -32.261 -7.635 1.263 1.00 0.00 <br />
ATOM 816 CD GLU A 107 -32.909 -8.302 0.067 1.00 0.00 <br />
ATOM 817 OE1 GLU A 107 -32.510 -9.436 -0.265 1.00 0.00 <br />
ATOM 818 OE2 GLU A 107 -33.806 -7.687 -0.549 1.00 0.00 <br />
TER<br />
ATOM 819 C1 RAP A 108 -18.510 -8.134 -11.063 1.00 0.00 <br />
ATOM 820 O1 RAP A 108 -18.969 -9.229 -11.856 1.00 0.00 <br />
ATOM 821 O2 RAP A 108 -17.819 -8.381 -10.069 1.00 0.00 <br />
ATOM 822 C2 RAP A 108 -18.857 -6.680 -11.413 1.00 0.00 <br />
ATOM 823 C3 RAP A 108 -19.378 -5.903 -10.192 1.00 0.00 <br />
ATOM 824 C4 RAP A 108 -20.810 -6.269 -9.768 1.00 0.00 <br />
ATOM 825 C5 RAP A 108 -21.748 -6.104 -10.968 1.00 0.00 <br />
ATOM 826 C6 RAP A 108 -21.289 -6.956 -12.126 1.00 0.00 <br />
ATOM 827 N7 RAP A 108 -19.893 -6.531 -12.486 1.00 0.00 <br />
ATOM 828 C8 RAP A 108 -19.513 -6.171 -13.744 1.00 0.00 <br />
ATOM 829 O3 RAP A 108 -18.296 -5.996 -13.976 1.00 0.00 <br />
ATOM 830 C9 RAP A 108 -20.424 -5.985 -14.822 1.00 0.00 <br />
ATOM 831 O4 RAP A 108 -21.015 -4.900 -14.935 1.00 0.00 <br />
ATOM 832 C10 RAP A 108 -20.701 -7.102 -15.860 1.00 0.00 <br />
ATOM 833 O5 RAP A 108 -21.536 -8.043 -15.186 1.00 0.00 <br />
ATOM 834 O6 RAP A 108 -21.405 -6.534 -16.979 1.00 0.00 <br />
ATOM 835 C11 RAP A 108 -19.388 -7.854 -16.375 1.00 0.00 <br />
ATOM 836 C12 RAP A 108 -19.775 -9.075 -17.246 1.00 0.00 <br />
ATOM 837 C13 RAP A 108 -20.761 -9.975 -16.480 1.00 0.00 <br />
ATOM 838 C14 RAP A 108 -21.967 -9.211 -15.854 1.00 0.00 <br />
ATOM 839 C15 RAP A 108 -22.672 -10.085 -14.824 1.00 0.00 <br />
ATOM 840 C16 RAP A 108 -23.453 -11.289 -15.379 1.00 0.00 <br />
ATOM 841 O7 RAP A 108 -24.420 -10.794 -16.279 1.00 0.00 <br />
ATOM 842 C17 RAP A 108 -24.142 -12.089 -14.269 1.00 0.00 <br />
ATOM 843 C18 RAP A 108 -23.665 -13.315 -13.987 1.00 0.00 <br />
ATOM 844 C19 RAP A 108 -24.201 -14.242 -12.966 1.00 0.00 <br />
ATOM 845 C20 RAP A 108 -23.630 -15.435 -12.786 1.00 0.00 <br />
ATOM 846 C21 RAP A 108 -24.162 -16.384 -11.781 1.00 0.00 <br />
ATOM 847 C22 RAP A 108 -23.444 -17.370 -11.268 1.00 0.00 <br />
ATOM 848 C23 RAP A 108 -23.906 -18.220 -10.081 1.00 0.00 <br />
ATOM 849 C24 RAP A 108 -22.851 -18.127 -8.963 1.00 0.00 <br />
ATOM 850 C25 RAP A 108 -22.360 -16.747 -8.519 1.00 0.00 <br />
ATOM 851 C26 RAP A 108 -21.023 -16.845 -7.774 1.00 0.00 <br />
ATOM 852 O8 RAP A 108 -20.965 -16.994 -6.547 1.00 0.00 <br />
ATOM 853 C27 RAP A 108 -19.745 -16.757 -8.633 1.00 0.00 <br />
ATOM 854 O9 RAP A 108 -18.698 -17.397 -7.951 1.00 0.00 <br />
ATOM 855 C28 RAP A 108 -19.234 -15.293 -8.931 1.00 0.00 <br />
ATOM 856 O10 RAP A 108 -19.259 -14.553 -7.701 1.00 0.00 <br />
ATOM 857 C29 RAP A 108 -20.070 -14.540 -10.006 1.00 0.00 <br />
ATOM 858 C30 RAP A 108 -20.851 -13.477 -9.720 1.00 0.00 <br />
ATOM 859 C31 RAP A 108 -21.739 -12.610 -10.632 1.00 0.00 <br />
ATOM 860 C32 RAP A 108 -21.031 -11.274 -10.909 1.00 0.00 <br />
ATOM 861 O11 RAP A 108 -21.295 -10.239 -10.286 1.00 0.00 <br />
ATOM 862 C33 RAP A 108 -19.966 -11.303 -12.008 1.00 0.00 <br />
ATOM 863 C34 RAP A 108 -18.698 -10.575 -11.585 1.00 0.00 <br />
ATOM 864 C35 RAP A 108 -17.359 -10.916 -12.304 1.00 0.00 <br />
ATOM 865 C36 RAP A 108 -16.786 -12.266 -11.815 1.00 0.00 <br />
ATOM 866 C37 RAP A 108 -16.322 -12.376 -10.346 1.00 0.00 <br />
ATOM 867 C38 RAP A 108 -15.790 -13.811 -10.060 1.00 0.00 <br />
ATOM 868 C39 RAP A 108 -15.278 -14.019 -8.595 1.00 0.00 <br />
ATOM 869 O12 RAP A 108 -14.646 -15.301 -8.504 1.00 0.00 <br />
ATOM 870 C40 RAP A 108 -14.253 -12.869 -8.176 1.00 0.00 <br />
ATOM 871 O13 RAP A 108 -14.019 -12.970 -6.766 1.00 0.00 <br />
ATOM 872 C41 RAP A 108 -14.775 -11.432 -8.497 1.00 0.00 <br />
ATOM 873 C42 RAP A 108 -15.251 -11.324 -9.952 1.00 0.00 <br />
ATOM 874 C43 RAP A 108 -18.390 -6.936 -17.162 1.00 0.00 <br />
ATOM 875 C44 RAP A 108 -25.350 -11.389 -13.580 1.00 0.00 <br />
ATOM 876 C45 RAP A 108 -24.081 -19.670 -10.522 1.00 0.00 <br />
ATOM 877 C46 RAP A 108 -23.414 -16.041 -7.644 1.00 0.00 <br />
ATOM 878 C47 RAP A 108 -19.924 -15.115 -11.414 1.00 0.00 <br />
ATOM 879 C48 RAP A 108 -23.101 -12.375 -9.939 1.00 0.00 <br />
ATOM 880 C49 RAP A 108 -17.519 -10.949 -13.817 1.00 0.00 <br />
ATOM 881 C50 RAP A 108 -24.780 -11.612 -17.353 1.00 0.00 <br />
ATOM 882 C51 RAP A 108 -18.394 -18.690 -8.368 1.00 0.00 <br />
ATOM 883 C52 RAP A 108 -13.537 -15.605 -9.312 1.00 0.00 <br />
ATOM 884 O MOL 1 -14.467 -0.075 1.713 1.00 0.00 <br />
ATOM 885 O MOL 1 -3.747 -10.364 -12.950 1.00 0.00 <br />
ATOM 886 O MOL 1 -3.863 1.423 -20.222 1.00 0.00 <br />
ATOM 887 O MOL 1 -33.153 2.955 -17.490 1.00 0.00 <br />
ATOM 888 O MOL 1 -11.437 -10.318 -9.024 1.00 0.00 <br />
ATOM 889 O MOL 1 -8.994 -5.070 -17.002 1.00 0.00 <br />
ATOM 890 O MOL 1 -16.599 7.684 0.589 1.00 0.00 <br />
ATOM 891 O MOL 1 -10.617 -3.779 -15.257 1.00 0.00 <br />
ATOM 892 O MOL 1 -7.744 -0.765 -21.451 1.00 0.00 <br />
ATOM 893 O MOL 1 -30.531 10.772 -1.245 1.00 0.00 <br />
ATOM 894 O MOL 1 -9.991 5.189 -8.561 1.00 0.00 <br />
ATOM 895 O MOL 1 -15.383 8.367 -8.819 1.00 0.00 <br />
ATOM 896 O MOL 1 -22.582 7.719 3.484 1.00 0.00 <br />
ATOM 897 O MOL 1 -31.535 6.282 3.044 1.00 0.00 <br />
ATOM 898 O MOL 1 -6.221 -11.354 -21.344 1.00 0.00 <br />
ATOM 899 O MOL 1 -30.986 8.365 -2.508 1.00 0.00 <br />
ATOM 900 O MOL 1 -26.122 5.808 -14.288 1.00 0.00 <br />
ATOM 901 O MOL 1 -28.681 6.587 -14.636 1.00 0.00 <br />
ATOM 902 O MOL 1 -30.242 9.407 -6.889 1.00 0.00 <br />
ATOM 903 O MOL 1 -4.086 -4.225 -12.418 1.00 0.00 <br />
ATOM 904 O MOL 1 -13.558 9.340 -12.463 1.00 0.00 <br />
ATOM 905 O MOL 1 -24.024 9.804 2.183 1.00 0.00 <br />
ATOM 906 O MOL 1 -28.911 -10.292 -8.292 1.00 0.00 <br />
ATOM 907 O MOL 1 -10.002 -11.107 -20.617 1.00 0.00 <br />
ATOM 908 O MOL 1 -3.379 -1.268 -11.644 1.00 0.00 <br />
ATOM 909 O MOL 1 -3.814 -6.433 -11.116 1.00 0.00 <br />
ATOM 910 O MOL 1 -6.811 1.796 -20.467 1.00 0.00 <br />
ATOM 911 O MOL 1 -5.042 0.450 -5.739 1.00 0.00 <br />
ATOM 912 O MOL 1 -13.226 8.110 -2.465 1.00 0.00 <br />
ATOM 913 O MOL 1 -11.705 -0.385 1.598 1.00 0.00 <br />
ATOM 914 O MOL 1 -26.811 -13.511 -10.984 1.00 0.00 <br />
ATOM 915 O MOL 1 -12.132 3.844 -1.192 1.00 0.00 <br />
ATOM 916 O MOL 1 -12.915 6.445 -0.256 1.00 0.00 <br />
ATOM 917 O MOL 1 -14.006 10.177 -15.559 1.00 0.00 <br />
ATOM 918 O MOL 1 -6.462 2.069 -16.582 1.00 0.00 <br />
ATOM 919 O MOL 1 -21.593 -5.761 -22.112 1.00 0.00 <br />
ATOM 920 O MOL 1 -22.112 4.659 11.361 1.00 0.00 <br />
ATOM 921 O MOL 1 -24.505 -7.743 -19.597 1.00 0.00 <br />
ATOM 922 O MOL 1 -2.660 -0.168 -14.034 1.00 0.00 <br />
ATOM 923 O MOL 1 -2.685 -8.544 -20.622 1.00 0.00 <br />
ATOM 924 O MOL 1 -30.204 4.761 -16.268 1.00 0.00 <br />
ATOM 925 O MOL 1 -1.421 1.865 -16.896 1.00 0.00 <br />
ATOM 926 O MOL 1 -22.558 11.507 0.921 1.00 0.00 <br />
ATOM 927 O MOL 1 -32.805 11.307 0.058 1.00 0.00 <br />
ATOM 928 O MOL 1 -3.446 -8.060 -13.318 1.00 0.00 <br />
ATOM 929 O MOL 1 -29.831 4.936 -9.378 1.00 0.00 <br />
ATOM 930 O MOL 1 -7.164 5.063 -13.547 1.00 0.00 <br />
ATOM 931 O MOL 1 -4.420 2.292 -14.820 1.00 0.00 <br />
ATOM 932 O MOL 1 -5.770 -9.954 -14.183 1.00 0.00 <br />
ATOM 933 O MOL 1 -27.557 -11.487 -9.884 1.00 0.00 <br />
ATOM 934 O MOL 1 -31.664 4.503 -2.445 1.00 0.00 <br />
ATOM 935 O MOL 1 -25.729 -8.264 -16.380 1.00 0.00 <br />
ATOM 936 O MOL 1 -21.969 10.396 5.765 1.00 0.00 <br />
ATOM 937 O MOL 1 -7.004 -0.510 -2.928 1.00 0.00 <br />
ATOM 938 O MOL 1 -30.875 7.805 -13.213 1.00 0.00 <br />
ATOM 939 O MOL 1 -18.401 12.641 -2.383 1.00 0.00 <br />
ATOM 940 O MOL 1 -18.898 -7.605 -25.486 1.00 0.00 <br />
ATOM 941 O MOL 1 -25.575 -5.788 -20.825 1.00 0.00 <br />
ATOM 942 O MOL 1 -7.654 5.064 -6.946 1.00 0.00 <br />
ATOM 943 O MOL 1 -10.256 -9.151 -22.336 1.00 0.00 <br />
ATOM 944 O MOL 1 -19.822 -4.848 -24.124 1.00 0.00 <br />
ATOM 945 O MOL 1 -23.526 -17.086 -4.354 1.00 0.00 <br />
ATOM 946 O MOL 1 -18.719 -10.494 -2.408 1.00 0.00 <br />
ATOM 947 O MOL 1 -17.490 -3.388 -23.343 1.00 0.00 <br />
ATOM 948 O MOL 1 -30.962 10.093 -11.750 1.00 0.00 <br />
ATOM 949 O MOL 1 -18.908 -1.315 -28.688 1.00 0.00 <br />
ATOM 950 O MOL 1 -3.124 -4.146 -15.431 1.00 0.00 <br />
ATOM 951 O MOL 1 -9.221 2.699 -18.647 1.00 0.00 <br />
ATOM 952 O MOL 1 -11.056 -7.239 -8.343 1.00 0.00 <br />
ATOM 953 O MOL 1 -13.633 -12.173 -15.090 1.00 0.00 <br />
ATOM 954 O MOL 1 -15.513 -10.202 -0.432 1.00 0.00 <br />
ATOM 955 O MOL 1 -28.234 2.974 -16.765 1.00 0.00 <br />
ATOM 956 O MOL 1 -15.150 1.628 -25.119 1.00 0.00 <br />
ATOM 957 O MOL 1 -27.057 11.649 5.648 1.00 0.00 <br />
ATOM 958 O MOL 1 -35.417 1.166 -8.176 1.00 0.00 <br />
ATOM 959 O MOL 1 -32.217 9.638 -9.089 1.00 0.00 <br />
ATOM 960 O MOL 1 -19.494 6.929 1.151 1.00 0.00 <br />
ATOM 961 O MOL 1 -9.252 2.616 -2.781 1.00 0.00 <br />
ATOM 962 O MOL 1 -24.348 -8.092 -23.126 1.00 0.00 <br />
ATOM 963 O MOL 1 -21.693 -7.243 -19.749 1.00 0.00 <br />
ATOM 964 O MOL 1 -11.065 8.058 -14.677 1.00 0.00 <br />
ATOM 965 O MOL 1 -21.355 0.992 -27.640 1.00 0.00 <br />
ATOM 966 O MOL 1 -8.191 6.228 -11.230 1.00 0.00 <br />
ATOM 967 O MOL 1 -1.738 -5.828 -9.719 1.00 0.00 <br />
ATOM 968 O MOL 1 -5.954 3.838 -4.110 1.00 0.00 <br />
ATOM 969 O MOL 1 -0.305 -0.954 -13.761 1.00 0.00 <br />
ATOM 970 O MOL 1 -35.121 9.765 -8.231 1.00 0.00 <br />
ATOM 971 O MOL 1 -9.195 7.921 -12.896 1.00 0.00 <br />
ATOM 972 O MOL 1 -11.412 -8.346 -24.443 1.00 0.00 <br />
ATOM 973 O MOL 1 -18.575 -4.730 5.949 1.00 0.00 <br />
ATOM 974 O MOL 1 -24.572 -2.651 -22.639 1.00 0.00 <br />
ATOM 975 O MOL 1 -17.538 -17.548 -1.182 1.00 0.00 <br />
ATOM 976 O MOL 1 -28.405 1.980 11.352 1.00 0.00 <br />
ATOM 977 O MOL 1 -27.591 2.765 -19.420 1.00 0.00 <br />
ATOM 978 O MOL 1 -17.468 7.579 -21.396 1.00 0.00 <br />
ATOM 979 O MOL 1 -31.391 9.463 3.968 1.00 0.00 <br />
ATOM 980 O MOL 1 -24.855 11.287 4.464 1.00 0.00 <br />
ATOM 981 O MOL 1 -32.329 -2.161 4.687 1.00 0.00 <br />
ATOM 982 O MOL 1 -31.502 -1.553 7.124 1.00 0.00 <br />
ATOM 983 O MOL 1 -5.167 -3.927 -5.363 1.00 0.00 <br />
ATOM 984 O MOL 1 -12.442 -12.583 -11.643 1.00 0.00 <br />
TER</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin </font size></font color> <sup>6,7</sup><br />
<br><br />
<br />
Rapamycin is a very complicated molecule. It had a 31 memembered ring, and also possesses many chiral centres, and different functional groups. Due to its complexity, it has proved a challenge to synthesise for many synthetic chemists. <br />
Methods have therefore been suggested, to prepare fragments of the molecule, and then combine them to get the total molecule of rapamycin.<br />
<br />
The first fragment prepared is the fragment from C<sub>10</sub> to C<sub>21</sub>. <br />
The starting material used is (R)-methyl 3-hydroxy-2-methylpropionate. This is converted to an alcohol in a four step reaction, as shown below:<br />
<br />
[[Image:synthesisstep.gif]]<br />
<br />
<br />
Then from this molecule, further complicated synthesis steps yield the following fragment:<br />
<br />
[[Image:Fragment1.gif]]<br />
<br />
<br />
The second fragment prepared is the fragment from C<sub>22</sub> - C<sub>42</sub>. This is prepared through complicated synthetic methods. The second fragment obtained is shown below:<br />
<br />
[[Image:Fragment2.gif]]<br />
<br />
The second fragment was then combined with the first fragment under certain required conditions, yielding the synthetic rapamycin, which was judged as identical to the natural occuring rapamycin molecule through comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.<br />
<br />
The various complicated synthesis steps, and conditions are all in the cited journals, from which this all synthetic information was gained.<br />
<br />
Rapamycin can also be synthesised by using trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH<sub>3</sub>CN)<sub>2</sub> C<sub>12</sub>, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
However, the starting material is hard to synthesise, so is usually only the fragment method of synthesis is used for synthetic rapamycin production<br />
<br />
<br />
<font size=5><font color=red>History</font size></font color><sup>10</sup><br><br />
<br><br />
Rapamycin is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a polyketide pathway. The polyketide chain is formed by condensation of seven acetate components and same number of propionate units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER CSD ENTRY QEKNID<br />
COMPND UNNAMED<br />
AUTHOR GENERATED BY CONQUEST<br />
CRYST1 20.690 22.560 11.220 90.00 90.00 90.00 P 21 21 21 4<br />
ATOM 1 O1 UNK 0 1 1.401 8.009 6.161 1.00 0.00<br />
ATOM 2 O2 UNK 0 1 1.535 9.421 3.430 1.00 0.00<br />
ATOM 3 O3 UNK 0 1 4.165 9.543 3.068 1.00 0.00<br />
ATOM 4 O4 UNK 0 1 6.290 5.800 0.411 1.00 0.00<br />
ATOM 5 O5 UNK 0 1 3.617 0.984 6.788 1.00 0.00<br />
ATOM 6 O6 UNK 0 1 1.988 4.661 5.821 1.00 0.00<br />
ATOM 7 O7 UNK 0 1 3.414 10.078 11.631 1.00 0.00<br />
ATOM 8 O8 UNK 0 1 4.926 9.642 9.448 1.00 0.00<br />
ATOM 9 O9 UNK 0 1 0.134 3.788 6.711 1.00 0.00<br />
ATOM 10 O10 UNK 0 1 8.545 -2.658 8.213 1.00 0.00<br />
ATOM 11 O11 UNK 0 1 3.877 7.255 3.373 1.00 0.00<br />
ATOM 12 O12 UNK 0 1 8.348 1.263 9.851 1.00 0.00<br />
ATOM 13 O13 UNK 0 1 9.710 -0.957 9.885 1.00 0.00<br />
ATOM 14 N1 UNK 0 1 0.821 6.574 4.485 1.00 0.00<br />
ATOM 15 C1 UNK 0 1 2.847 3.804 6.597 1.00 0.00<br />
ATOM 16 C2 UNK 0 1 2.137 8.591 4.006 1.00 0.00<br />
ATOM 17 C3 UNK 0 1 5.253 5.566 2.525 1.00 0.00<br />
ATOM 18 C4 UNK 0 1 6.439 0.772 7.035 1.00 0.00<br />
ATOM 19 C5 UNK 0 1 5.760 1.455 5.879 1.00 0.00<br />
ATOM 20 C6 UNK 0 1 3.691 8.555 3.927 1.00 0.00<br />
ATOM 21 C7 UNK 0 1 4.372 8.706 5.296 1.00 0.00<br />
ATOM 22 C8 UNK 0 1 0.685 4.598 6.025 1.00 0.00<br />
ATOM 23 C9 UNK 0 1 1.444 7.657 4.993 1.00 0.00<br />
ATOM 24 C10 UNK 0 1 5.266 6.987 3.074 1.00 0.00<br />
ATOM 25 C11 UNK 0 1 9.484 1.514 2.917 1.00 0.00<br />
ATOM 26 C12 UNK 0 1 6.546 5.254 1.728 1.00 0.00<br />
ATOM 27 C13 UNK 0 1 0.002 5.764 5.363 1.00 0.00<br />
ATOM 28 C14 UNK 0 1 6.873 3.770 1.616 1.00 0.00<br />
ATOM 29 C15 UNK 0 1 5.845 8.444 5.027 1.00 0.00<br />
ATOM 30 C16 UNK 0 1 4.643 3.941 8.471 1.00 0.00<br />
ATOM 31 C17 UNK 0 1 4.175 10.062 5.891 1.00 0.00<br />
ATOM 32 C18 UNK 0 1 6.062 7.106 4.353 1.00 0.00<br />
ATOM 33 C19 UNK 0 1 1.130 5.996 3.130 1.00 0.00<br />
ATOM 34 C20 UNK 0 1 0.132 5.568 2.424 1.00 0.00<br />
ATOM 35 C21 UNK 0 1 -0.902 4.584 3.310 1.00 0.00<br />
ATOM 36 C22 UNK 0 1 -1.283 5.277 4.634 1.00 0.00<br />
ATOM 37 C23 UNK 0 1 7.333 5.703 -0.449 1.00 0.00<br />
ATOM 38 C24 UNK 0 1 5.787 2.858 0.987 1.00 0.00<br />
ATOM 39 C25 UNK 0 1 4.223 8.521 10.019 1.00 0.00<br />
ATOM 40 C26 UNK 0 1 3.070 9.096 10.659 1.00 0.00<br />
ATOM 41 C27 UNK 0 1 2.162 8.038 11.321 1.00 0.00<br />
ATOM 42 C28 UNK 0 1 1.777 7.000 10.322 1.00 0.00<br />
ATOM 43 C29 UNK 0 1 3.035 6.371 9.593 1.00 0.00<br />
ATOM 44 C30 UNK 0 1 3.813 7.463 8.954 1.00 0.00<br />
ATOM 45 C31 UNK 0 1 4.299 1.800 6.149 1.00 0.00<br />
ATOM 46 C32 UNK 0 1 3.745 3.070 5.621 1.00 0.00<br />
ATOM 47 C33 UNK 0 1 2.489 5.369 8.538 1.00 0.00<br />
ATOM 48 C34 UNK 0 1 3.534 4.692 7.641 1.00 0.00<br />
ATOM 49 C35 UNK 0 1 8.028 3.321 2.132 1.00 0.00<br />
ATOM 50 C36 UNK 0 1 8.423 1.922 2.255 1.00 0.00<br />
ATOM 51 C37 UNK 0 1 10.751 -0.223 3.994 1.00 0.00<br />
ATOM 52 C38 UNK 0 1 10.968 -1.676 4.387 1.00 0.00<br />
ATOM 53 C39 UNK 0 1 12.420 -1.994 4.107 1.00 0.00<br />
ATOM 54 C40 UNK 0 1 10.657 -1.852 5.891 1.00 0.00<br />
ATOM 55 C41 UNK 0 1 9.215 -1.475 6.205 1.00 0.00<br />
ATOM 56 C42 UNK 0 1 9.846 0.140 3.119 1.00 0.00<br />
ATOM 57 C43 UNK 0 1 8.266 -2.391 5.430 1.00 0.00<br />
ATOM 58 C44 UNK 0 1 9.019 -1.694 7.697 1.00 0.00<br />
ATOM 59 C45 UNK 0 1 8.460 2.175 7.057 1.00 0.00<br />
ATOM 60 C46 UNK 0 1 6.296 9.389 9.133 1.00 0.00<br />
ATOM 61 C47 UNK 0 1 9.362 -0.492 8.583 1.00 0.00<br />
ATOM 62 C48 UNK 0 1 10.976 -0.887 10.210 1.00 0.00<br />
ATOM 63 C49 UNK 0 1 8.108 0.334 8.785 1.00 0.00<br />
ATOM 64 C50 UNK 0 1 7.606 1.060 7.562 1.00 0.00<br />
ATOM 65 C51 UNK 0 1 5.843 0.575 4.600 1.00 0.00<br />
ATOM 66 H1 UNK 0 1 3.540 9.985 2.615 1.00 0.00<br />
ATOM 67 H2 UNK 0 1 8.210 2.112 9.513 1.00 0.00<br />
ATOM 68 H3 UNK 0 1 5.710 0.147 7.313 1.00 0.00<br />
ATOM 69 H4 UNK 0 1 6.224 2.351 5.476 1.00 0.00<br />
ATOM 70 H5 UNK 0 1 4.030 7.758 6.075 1.00 0.00<br />
ATOM 71 H6 UNK 0 1 10.151 2.085 3.193 1.00 0.00<br />
ATOM 72 H7 UNK 0 1 6.188 9.139 4.429 1.00 0.00<br />
ATOM 73 H8 UNK 0 1 4.260 3.370 9.108 1.00 0.00<br />
ATOM 74 H9 UNK 0 1 3.269 10.154 6.217 1.00 0.00<br />
ATOM 75 H10 UNK 0 1 6.999 6.982 4.170 1.00 0.00<br />
ATOM 76 H11 UNK 0 1 1.572 6.664 2.602 1.00 0.00<br />
ATOM 77 H12 UNK 0 1 -1.748 4.645 5.196 1.00 0.00<br />
ATOM 78 H13 UNK 0 1 5.371 3.343 0.286 1.00 0.00<br />
ATOM 79 H14 UNK 0 1 1.608 6.177 10.770 1.00 0.00<br />
ATOM 80 H15 UNK 0 1 3.428 5.947 10.188 1.00 0.00<br />
ATOM 81 H16 UNK 0 1 4.802 7.221 8.586 1.00 0.00<br />
ATOM 82 H17 UNK 0 1 3.548 7.930 8.237 1.00 0.00<br />
ATOM 83 H18 UNK 0 1 3.271 2.897 4.825 1.00 0.00<br />
ATOM 84 H19 UNK 0 1 1.879 5.827 7.973 1.00 0.00<br />
ATOM 85 H20 UNK 0 1 3.960 5.331 7.139 1.00 0.00<br />
ATOM 86 H21 UNK 0 1 8.382 3.858 2.781 1.00 0.00<br />
ATOM 87 H22 UNK 0 1 10.258 -2.409 3.883 1.00 0.00<br />
ATOM 88 H23 UNK 0 1 12.704 -2.786 4.518 1.00 0.00<br />
ATOM 89 H24 UNK 0 1 10.659 -2.732 5.892 1.00 0.00<br />
ATOM 90 H25 UNK 0 1 11.239 -1.078 6.572 1.00 0.00<br />
ATOM 91 H26 UNK 0 1 9.195 -0.305 5.991 1.00 0.00<br />
ATOM 92 H27 UNK 0 1 9.112 -0.650 2.517 1.00 0.00<br />
ATOM 93 H28 UNK 0 1 8.466 -3.298 5.647 1.00 0.00<br />
ATOM 94 H29 UNK 0 1 8.322 2.955 7.548 1.00 0.00<br />
ATOM 95 H30 UNK 0 1 6.714 10.132 8.706 1.00 0.00<br />
ATOM 96 H31 UNK 0 1 6.391 8.622 8.547 1.00 0.00<br />
ATOM 97 H32 UNK 0 1 7.293 -0.210 9.074 1.00 0.00<br />
ATOM 98 H33 UNK 0 1 5.866 -0.356 4.865 1.00 0.00<br />
ATOM 99 H34 UNK 0 1 5.183 4.941 3.258 1.00 0.00<br />
ATOM 100 H35 UNK 0 1 7.519 4.789 -0.649 1.00 0.00<br />
ATOM 101 H36 UNK 0 1 7.190 6.184 -1.241 1.00 0.00<br />
ATOM 102 H37 UNK 0 1 1.328 7.208 9.650 1.00 0.00<br />
ATOM 103 H38 UNK 0 1 8.011 1.087 1.694 1.00 0.00<br />
ATOM 104 H39 UNK 0 1 12.617 -2.003 3.181 1.00 0.00<br />
ATOM 105 H40 UNK 0 1 7.366 -2.209 5.718 1.00 0.00<br />
ATOM 106 H41 UNK 0 1 11.307 0.449 4.388 1.00 0.00<br />
ATOM 107 H42 UNK 0 1 -0.679 6.317 2.243 1.00 0.00<br />
ATOM 108 H43 UNK 0 1 0.095 5.141 1.592 1.00 0.00<br />
ATOM 109 H44 UNK 0 1 5.144 2.624 1.641 1.00 0.00<br />
ATOM 110 H45 UNK 0 1 6.209 2.089 0.650 1.00 0.00<br />
ATOM 111 H46 UNK 0 1 -1.872 6.010 4.470 1.00 0.00<br />
ATOM 112 H47 UNK 0 1 1.713 5.252 3.228 1.00 0.00<br />
ATOM 113 H48 UNK 0 1 -0.294 6.351 6.059 1.00 0.00<br />
ATOM 114 H49 UNK 0 1 5.175 3.393 7.855 1.00 0.00<br />
ATOM 115 H50 UNK 0 1 5.228 4.559 8.877 1.00 0.00<br />
ATOM 116 H51 UNK 0 1 2.023 4.681 9.009 1.00 0.00<br />
ATOM 117 H52 UNK 0 1 1.378 8.478 11.672 1.00 0.00<br />
ATOM 118 H53 UNK 0 1 2.549 9.527 9.980 1.00 0.00<br />
ATOM 119 H54 UNK 0 1 4.759 8.106 10.676 1.00 0.00<br />
ATOM 120 H55 UNK 0 1 6.811 9.184 9.931 1.00 0.00<br />
ATOM 121 H56 UNK 0 1 3.064 10.019 12.513 1.00 0.00<br />
ATOM 122 H57 UNK 0 1 5.046 0.704 4.082 1.00 0.00<br />
ATOM 123 H58 UNK 0 1 6.596 0.778 4.098 1.00 0.00<br />
ATOM 124 H59 UNK 0 1 9.391 1.922 7.099 1.00 0.00<br />
ATOM 125 H60 UNK 0 1 8.249 2.330 6.128 1.00 0.00<br />
ATOM 126 H61 UNK 0 1 11.301 -0.034 10.172 1.00 0.00<br />
ATOM 127 H62 UNK 0 1 8.344 -2.245 4.515 1.00 0.00<br />
ATOM 128 H63 UNK 0 1 12.991 -1.261 4.491 1.00 0.00<br />
ATOM 129 H64 UNK 0 1 7.291 5.701 2.119 1.00 0.00<br />
ATOM 130 H65 UNK 0 1 4.496 5.446 1.961 1.00 0.00<br />
ATOM 131 H66 UNK 0 1 5.609 7.596 2.424 1.00 0.00<br />
ATOM 132 H67 UNK 0 1 6.352 8.496 5.832 1.00 0.00<br />
ATOM 133 H68 UNK 0 1 4.769 10.215 6.611 1.00 0.00<br />
ATOM 134 H69 UNK 0 1 4.308 10.741 5.225 1.00 0.00<br />
ATOM 135 H70 UNK 0 1 2.319 3.147 7.060 1.00 0.00<br />
ATOM 136 H71 UNK 0 1 5.793 6.418 4.966 1.00 0.00<br />
ATOM 137 H72 UNK 0 1 -1.823 4.302 2.821 1.00 0.00<br />
ATOM 138 H73 UNK 0 1 -0.339 3.831 3.457 1.00 0.00<br />
ATOM 139 H74 UNK 0 1 8.137 6.064 -0.019 1.00 0.00<br />
ATOM 140 H75 UNK 0 1 2.630 7.650 12.060 1.00 0.00<br />
ATOM 141 H76 UNK 0 1 4.498 3.646 5.411 1.00 0.00<br />
ATOM 142 H77 UNK 0 1 11.137 -1.200 11.098 1.00 0.00<br />
ATOM 143 H78 UNK 0 1 11.531 -1.392 9.609 1.00 0.00<br />
ATOM 144 H79 UNK 0 1 10.095 0.059 8.192 1.00 0.00<br />
ATOM 145 H80 UNK 0 1 6.443 3.641 2.498 1.00 0.00<br />
CONECT 1 23<br />
CONECT 2 16<br />
CONECT 3 20 66<br />
CONECT 4 26 37<br />
CONECT 5 45<br />
CONECT 6 15 22<br />
CONECT 7 40 121<br />
CONECT 8 39 60<br />
CONECT 9 22<br />
CONECT 10 58<br />
CONECT 11 20 24<br />
CONECT 12 63 67<br />
CONECT 13 61 62<br />
CONECT 14 23 27 33<br />
CONECT 15 6 46 48 135<br />
CONECT 16 2 20 23<br />
CONECT 17 24 26 99 130<br />
CONECT 18 19 64 68<br />
CONECT 19 18 45 65 69<br />
CONECT 20 3 11 16 21<br />
CONECT 21 20 29 31 70<br />
CONECT 22 6 9 27<br />
CONECT 23 1 14 16<br />
CONECT 24 11 17 32 131<br />
CONECT 25 50 56 71<br />
CONECT 26 4 17 28 129<br />
CONECT 27 14 22 36 113<br />
CONECT 28 26 38 49<br />
CONECT 29 21 32 72 132<br />
CONECT 30 48 73 114 115<br />
CONECT 31 21 74 133 134<br />
CONECT 32 24 29 75 136<br />
CONECT 33 14 34 76 112<br />
CONECT 34 33 35 107 108<br />
CONECT 35 34 36 137 138<br />
CONECT 36 27 35 77 111<br />
CONECT 37 4 100 101 139<br />
CONECT 38 28 78 109 110<br />
CONECT 39 8 40 44 119<br />
CONECT 40 7 39 41 118<br />
CONECT 41 40 42 117 140<br />
CONECT 42 41 43 79 102<br />
CONECT 43 42 44 47 80<br />
CONECT 44 39 43 81 82<br />
CONECT 45 5 19 46<br />
CONECT 46 15 45 83 141<br />
CONECT 47 43 48 84 116<br />
CONECT 48 15 30 47 85<br />
CONECT 49 28 50 86<br />
CONECT 50 25 49 103<br />
CONECT 51 52 56 106<br />
CONECT 52 51 53 54 87<br />
CONECT 53 52 88 104 128<br />
CONECT 54 52 55 89 90<br />
CONECT 55 54 57 58 91<br />
CONECT 56 25 51 92<br />
CONECT 57 55 93 105 127<br />
CONECT 58 10 55 61<br />
CONECT 59 64 94 124 125<br />
CONECT 60 8 95 96 120<br />
CONECT 61 13 58 63 144<br />
CONECT 62 13 126 142 143<br />
CONECT 63 12 61 64 97<br />
CONECT 64 18 59 63<br />
CONECT 65 19 98 122 123<br />
CONECT 66 3<br />
CONECT 67 12<br />
CONECT 68 18<br />
CONECT 69 19<br />
CONECT 70 21<br />
CONECT 71 25<br />
CONECT 72 29<br />
CONECT 73 30<br />
CONECT 74 31<br />
CONECT 75 32<br />
CONECT 76 33<br />
CONECT 77 36<br />
CONECT 78 38<br />
CONECT 79 42<br />
CONECT 80 43<br />
CONECT 81 44<br />
CONECT 82 44<br />
CONECT 83 46<br />
CONECT 84 47<br />
CONECT 85 48<br />
CONECT 86 49<br />
CONECT 87 52<br />
CONECT 88 53<br />
CONECT 89 54<br />
CONECT 90 54<br />
CONECT 91 55<br />
CONECT 92 56<br />
CONECT 93 57<br />
CONECT 94 59<br />
CONECT 95 60<br />
CONECT 96 60<br />
CONECT 97 63<br />
CONECT 98 65<br />
CONECT 99 17<br />
CONECT 100 37<br />
CONECT 101 37<br />
CONECT 102 42<br />
CONECT 103 50<br />
CONECT 104 53<br />
CONECT 105 57<br />
CONECT 106 51<br />
CONECT 107 34<br />
CONECT 108 34<br />
CONECT 109 38<br />
CONECT 110 38<br />
CONECT 111 36<br />
CONECT 112 33<br />
CONECT 113 27<br />
CONECT 114 30<br />
CONECT 115 30<br />
CONECT 116 47<br />
CONECT 117 41<br />
CONECT 118 40<br />
CONECT 119 39<br />
CONECT 120 60<br />
CONECT 121 7<br />
CONECT 122 65<br />
CONECT 123 65<br />
CONECT 124 59<br />
CONECT 125 59<br />
CONECT 126 62<br />
CONECT 127 57<br />
CONECT 128 53<br />
CONECT 129 26<br />
CONECT 130 17<br />
CONECT 131 24<br />
CONECT 132 29<br />
CONECT 133 31<br />
CONECT 134 31<br />
CONECT 135 15<br />
CONECT 136 32<br />
CONECT 137 35<br />
CONECT 138 35<br />
CONECT 139 37<br />
CONECT 140 41<br />
CONECT 141 46<br />
CONECT 142 62<br />
CONECT 143 62<br />
CONECT 144 61<br />
CONECT 145 0<br />
MASTER 0 0 0 0 0 0 0 0 145 0 145 0<br />
END</inlineContents><br />
</jmolApplet><br />
</jmol><br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br><br />
6) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato; J. Am. Chem. Soc.; 115; 1993; 4419-4420 <br><br />
7) D. Romo, D. D. Johnson, L. Plamondon, T. Miwa, S. L. Schreiber; J. Org. Chem.; 57; 1992; 5060-5063 <br><br />
8) http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
9) ''How Rapamycin works'' diagram taken from http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
10) http://www.rapamycin.org/rapamycin.html<br><br />
11) ''3D structure of the binding protein, <br />
FKBP 12.6 in complex with a rapamycin molecule'' <br />
image taken from http://www.rcsb.org/pdb/explore.do?structureId=1C9H</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=File:Qeknid.pdb&diff=4219
File:Qeknid.pdb
2006-10-26T13:25:58Z
<p>Qlw05: Rapamycin 3D structure</p>
<hr />
<div>Rapamycin 3D structure</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4186
It:Rapamycin
2006-10-26T12:50:31Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:Rapamycin.gif|50|2D structure of Rapamycin|50]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
The rapamycin is thought to target the proteins <sup>8</sup>:<br />
(1) 70-kD S6 protein kinase p70<sup>S6K</sup><br />
(2) Eukaryotic initiation factor eIF-4F<br />
(3) G1-controlling cyclin-dependent kinase (cdk) proteins <br />
(4) Kinase inhibitory protein Kip1 (p27<sup>kip</sup>), which blocks cell progression to the S phase.<br />
<br />
The diagram below shows how the mechanism steps of how rapamycin works:<br />
<br />
'''How Rapamycin works'''<br />
[[Image:mechanism.gif]]<br />
<br />
''Note:''<br />
SRL = Sirolimus (rapamycin)<br />
mTOR = mammalian target of rapamycin<br />
CsA = Cyclosporine<br />
PTKs = protein tyrosine kinases<br />
p34<sup>cdc2</sup> = a kinase<br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin </font size></font color> <sup>6,7</sup><br />
<br><br />
<br />
Rapamycin is a very complicated molecule. It had a 31 memembered ring, and also possesses many chiral centres, and different functional groups. Due to its complexity, it has proved a challenge to synthesise for many synthetic chemists. <br />
Methods have therefore been suggested, to prepare fragments of the molecule, and then combine them to get the total molecule of rapamycin.<br />
<br />
The first fragment prepared is the fragment from C<sub>10</sub> to C<sub>21</sub>. <br />
The starting material used is (R)-methyl 3-hydroxy-2-methylpropionate. This is converted to an alcohol in a four step reaction, as shown below:<br />
<br />
[[Image:synthesisstep.gif]]<br />
<br />
<br />
Then from this molecule, further complicated synthesis steps yield the following fragment:<br />
<br />
[[Image:Fragment1.gif]]<br />
<br />
<br />
The second fragment prepared is the fragment from C<sub>22</sub> - C<sub>42</sub>. This is prepared through complicated synthetic methods. The second fragment obtained is shown below:<br />
<br />
[[Image:Fragment2.gif]]<br />
<br />
The second fragment was then combined with the first fragment under certain required conditions, yielding the synthetic rapamycin, which was judged as identical to the natural occuring rapamycin molecule through comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.<br />
<br />
The various complicated synthesis steps, and conditions are all in the cited journals, from which this all synthetic information was gained.<br />
<br />
Rapamycin can also be synthesised by using trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH<sub>3</sub>CN)<sub>2</sub> C<sub>12</sub>, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
However, the starting material is hard to synthesise, so is usually only the fragment method of synthesis is used for synthetic rapamycin production<br />
<br />
<br />
<font size=5><font color=red>History</font size></font color><sup>10</sup><br><br />
<br><br />
Rapamycin is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a polyketide pathway. The polyketide chain is formed by condensation of seven acetate components and same number of propionate units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br><br />
6) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato; J. Am. Chem. Soc.; 115; 1993; 4419-4420 <br><br />
7) D. Romo, D. D. Johnson, L. Plamondon, T. Miwa, S. L. Schreiber; J. Org. Chem.; 57; 1992; 5060-5063 <br><br />
8) http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
9) ''How Rapamycin works'' diagram taken from http://www-ermm.cbcu.cam.ac.uk/00001794h.htm <br><br />
10)http://www.rapamycin.org/rapamycin.html<br></div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Retinal&diff=4174
It:Retinal
2006-10-26T12:43:34Z
<p>Qlw05: </p>
<hr />
<div>__toc__<br />
<br />
'''Retinal''', also known as retinaldehyde or retinene<sub>1</sub> is the most important molecule associated with vision. Retinal changes structure when it is exposed to light, essentially transferring the energy from the light it absorbs to an electrical impulse in the retina of the eye, which is then passed along the optic nerve to the central nervous system to be processed. All vision systems operate in this manner, so Retinal is resposible for all vision. Retinal is a retinine molecule that exists as two different isomers - 11-cis retinal and all-trans retinal.<br />
<br />
== Structure of Cis-Retinal ==<br />
<br />
{| class="toccolours" border="0" style="fix: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" bgcolor="lt blue"|'''2D Structure'''<br />
| align="center" bgcolor="lt blue"|'''3D Structure'''<br />
|-<br />
| [[image:Cis-RetinalSo.gif]]<br />
|<jmol><br />
<jmolApplet><br />
<size>350</size><br />
<color>white</color><br />
<script>zoom 100; bns on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
HEADER NONAME 23-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 23-Oct-06 0 NONE 4<br />
ATOM 1 O 0 -4.284 3.090 -0.370 0.00 0.00 O+0<br />
ATOM 2 C 0 -4.565 2.093 0.267 0.00 0.00 C+0<br />
ATOM 3 H 0 -5.014 2.185 1.244 0.00 0.00 H+0<br />
ATOM 4 C 0 -4.301 0.826 -0.264 0.00 0.00 C+0<br />
ATOM 5 H 0 -3.848 0.734 -1.240 0.00 0.00 H+0<br />
ATOM 6 C 0 -4.620 -0.304 0.458 0.00 0.00 C+0<br />
ATOM 7 C 0 -5.252 -0.175 1.820 0.00 0.00 C+0<br />
ATOM 8 H 0 -5.510 -1.165 2.196 0.00 0.00 H+0<br />
ATOM 9 H 0 -4.549 0.302 2.503 0.00 0.00 H+0<br />
ATOM 10 H 0 -6.155 0.431 1.745 0.00 0.00 H+0<br />
ATOM 11 C 0 -4.356 -1.571 -0.074 0.00 0.00 C+0<br />
ATOM 12 H 0 -5.156 -2.288 -0.184 0.00 0.00 H+0<br />
ATOM 13 C 0 -3.075 -1.905 -0.455 0.00 0.00 C+0<br />
ATOM 14 H 0 -2.888 -2.841 -0.961 0.00 0.00 H+0<br />
ATOM 15 C 0 -2.013 -1.030 -0.187 0.00 0.00 C+0<br />
ATOM 16 H 0 -2.209 -0.062 0.250 0.00 0.00 H+0<br />
ATOM 17 C 0 -0.732 -1.401 -0.480 0.00 0.00 C+0<br />
ATOM 18 C 0 -0.460 -2.751 -1.091 0.00 0.00 C+0<br />
ATOM 19 H 0 0.617 -2.905 -1.166 0.00 0.00 H+0<br />
ATOM 20 H 0 -0.895 -3.529 -0.463 0.00 0.00 H+0<br />
ATOM 21 H 0 -0.903 -2.796 -2.086 0.00 0.00 H+0<br />
ATOM 22 C 0 0.332 -0.523 -0.212 0.00 0.00 C+0<br />
ATOM 23 H 0 0.148 0.407 0.306 0.00 0.00 H+0<br />
ATOM 24 C 0 1.593 -0.845 -0.603 0.00 0.00 C+0<br />
ATOM 25 H 0 1.769 -1.745 -1.174 0.00 0.00 H+0<br />
ATOM 26 C 0 2.679 0.001 -0.262 0.00 0.00 C+0<br />
ATOM 27 C 0 2.629 1.266 -0.646 0.00 0.00 C+0<br />
ATOM 28 C 0 1.416 1.729 -1.413 0.00 0.00 C+0<br />
ATOM 29 H 0 0.676 2.124 -0.718 0.00 0.00 H+0<br />
ATOM 30 H 0 1.708 2.509 -2.116 0.00 0.00 H+0<br />
ATOM 31 H 0 0.989 0.888 -1.959 0.00 0.00 H+0<br />
ATOM 32 C 0 3.711 2.266 -0.361 0.00 0.00 C+0<br />
ATOM 33 H 0 4.301 2.427 -1.263 0.00 0.00 H+0<br />
ATOM 34 H 0 3.259 3.209 -0.052 0.00 0.00 H+0<br />
ATOM 35 C 0 4.621 1.753 0.756 0.00 0.00 C+0<br />
ATOM 36 H 0 4.080 1.760 1.702 0.00 0.00 H+0<br />
ATOM 37 H 0 5.501 2.391 0.833 0.00 0.00 H+0<br />
ATOM 38 C 0 5.048 0.319 0.417 0.00 0.00 C+0<br />
ATOM 39 H 0 5.449 0.286 -0.595 0.00 0.00 H+0<br />
ATOM 40 H 0 5.809 -0.013 1.124 0.00 0.00 H+0<br />
ATOM 41 C 0 3.817 -0.587 0.519 0.00 0.00 C+0<br />
ATOM 42 C 0 3.414 -0.733 1.988 0.00 0.00 C+0<br />
ATOM 43 H 0 3.178 0.249 2.399 0.00 0.00 H+0<br />
ATOM 44 H 0 2.538 -1.377 2.062 0.00 0.00 H+0<br />
ATOM 45 H 0 4.238 -1.173 2.549 0.00 0.00 H+0<br />
ATOM 46 C 0 4.155 -1.967 -0.050 0.00 0.00 C+0<br />
ATOM 47 H 0 4.922 -2.436 0.566 0.00 0.00 H+0<br />
ATOM 48 H 0 3.260 -2.589 -0.051 0.00 0.00 H+0<br />
ATOM 49 H 0 4.524 -1.859 -1.070 0.00 0.00 H+0<br />
CONECT 1 2 0 0 0 NONE 54<br />
CONECT 2 1 3 4 0 NONE 55<br />
CONECT 4 2 5 6 0 NONE 56<br />
CONECT 6 4 7 11 0 NONE 57<br />
CONECT 7 6 8 9 10 NONE 58<br />
CONECT 11 6 12 13 0 NONE 59<br />
CONECT 13 11 14 15 0 NONE 60<br />
CONECT 15 13 16 17 0 NONE 61<br />
CONECT 17 15 18 22 0 NONE 62<br />
CONECT 18 17 19 20 21 NONE 63<br />
CONECT 22 17 23 24 0 NONE 64<br />
CONECT 24 22 25 26 0 NONE 65<br />
CONECT 26 24 41 27 0 NONE 66<br />
CONECT 27 26 28 32 0 NONE 67<br />
CONECT 28 27 29 30 31 NONE 68<br />
CONECT 32 27 33 34 35 NONE 69<br />
CONECT 35 32 36 37 38 NONE 70<br />
CONECT 38 35 39 40 41 NONE 71<br />
CONECT 41 38 26 42 46 NONE 72<br />
CONECT 42 41 43 44 45 NONE 73<br />
CONECT 46 41 47 48 49 NONE 74<br />
END NONE 75<br />
NONE 70<br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|}<br />
<br />
== Properties of Cis-Retinal and Trans-Retinal ==<br />
<br />
{| class="toccolours" border="1" style="fix : right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
|-<br />
| align="center" colspan="1" bgcolor="lt blue"|<br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Cis-Retinal''' <br />
| align="center" colspan="1" bgcolor="lt blue"|'''Properties of Trans-Retinal''' <br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''General properties''' <br />
|-<br />
| Chemical name<br />
| align="center"|(11Z)-retinal<br />
| align="center"|...<br />
|-<br />
| Chemical formula<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
| align="center"|C<sub>20</sub>H<sub>28</sub>O<br />
|-<br />
| Molecular mass<br />
| align="center"|284 g/mol<br />
| align="center"|284 g/mol<br />
|-<br />
| align="center" colspan="3" bgcolor="white"|'''Physical properties'''<br />
|-<br />
| Melting point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Boiling point<br />
| align="center"|... °C<br />
| align="center"|... °C<br />
|-<br />
| Appearance<br />
| align="center"|...<br />
| align="center"|...<br />
|-<br />
| align="center" colspan="3" bgcolor="white" |'''Miscelleneous'''<br />
|-<br />
| SMILES<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C\C(C)=C\C=O)<br />
=C(C)CCC1<br />
| align="center"|CC1(C)C(/C=C/C(C)=C/C=C/C(C)=C/C=O)<br />
=C(C)CCC1<br />
|-<br />
|}<br />
<br />
==Structure of all-trans retinal==<br />
'''2D Structure'''<br />
<br />
[[Image:AllTransRetinal.gif]]<br />
<br />
<br />
<br />
==The role of retinal in the vision process==<br />
<br />
The molecule that takes part in the vision process is rhodopsin which consists of 11-cis retinal and protein opsin. Retinal is a Vitamin A derivative. When there is no light present the 11-cis retinal has a bent configuration and is attached to the retinal molecule in a stable arrangement. When light strikes the retina, the retinal molecule absorbs a photon into one of the pi-bonds between the 11th and 12th carbon atoms, hence the 11 cis retinal is transfformed into the all trans retinal.<br />
<br />
[[Image:RetinalConversion.png]]<br />
<br />
==Synthesis of Rhodopsin==<br />
[[Image:Synthesis_of_rhodopsin.gif]]<br />
<br />
==Effects of Bunazosin on ocular circulation and retinal neuronal damage==<br />
<br />
By applying bunazosin hydrochloride into a healthy humans, it increases the blood velocity in the optic nerve head(ONH),retina and choroid, without changing either heart rate and blood pressure dramaticallt. This drup also applied to rabit and rat which gave positive results. These shows that bunazosin hydrochloride have improvement effect both in the ocular circulation and a direct neuroprotective effct. Therefore, it may be useful to use bunazosin hydrochloride as a therapeutic drug against retinal diseases which is associated with the ocular circulation.<br />
<br />
<br />
<br />
== References ==<br />
<br />
*Beilstein Data: Copyright (c) 1988-2006, Beilstein institut zur Foerderung der Chemischen Wissenschaften licensed to Beilstein GmBH and MDL information systems GmbH<br />
<br />
*1.Chang, Raymond (1998). Chemistry, 6th Ed.. New York: McGraw Hill. ISBN 0-07-115221-0. <br />
*2. Feynman, Richard (1985). QED - The Strange Theory of Light and Matter. Princeton, New Jersey: Princeton University Press. ISBN 0691024170.<br />
*3.Hara, Hideaki / Ichikawa, Masaki / Oku, Hidehiro / Shimazawa, Masamitsu / Araie, Makoto, Cardiovascular drug reviews, Apr 2005</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4163
It:Rapamycin
2006-10-26T12:03:08Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:Rapamycin.gif|50|2D structure of Rapamycin|50]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin </font size></font color> <sup>6,7</sup><br />
<br><br />
<br />
Rapamycin is a very complicated molecule. It had a 31 memembered ring, and also possesses many chiral centres, and different functional groups. Due to its complexity, it has proved a challenge to synthesise for many synthetic chemists. <br />
Methods have therefore been suggested, to prepare fragments of the molecule, and then combine them to get the total molecule of rapamycin.<br />
<br />
The first fragment prepared is the fragment from C<sub>10</sub> to C<sub>21</sub>. <br />
The starting material used is (R)-methyl 3-hydroxy-2-methylpropionate. This is converted to an alcohol in a four step reaction, as shown below:<br />
<br />
[[Image:synthesisstep.gif]]<br />
<br />
Then from this molecule, further complicated synthesis steps yield the following fragment:<br />
<br />
[[Image:Fragment1.gif]]<br />
<br />
The second fragment prepared is the fragment from C<sub>22</sub> - C<sub>42</sub>. This is prepared through complicated synthetic methods. The second fragment obtained is shown below:<br />
<br />
[[Image:Fragment2.gif]]<br />
<br />
The second fragment was then combined with the first fragment under certain required conditions, yielding the synthetic rapamycin, which was judged as identical to the natural occuring rapamycin molecule through comparison of physical properties, 1H-NMR, 13C-NMR, IR and UV spectral data.<br />
<br />
The various complicated synthesis steps, and conditions are all in the cited journals, from which this all synthetic information was gained.<br />
<br />
Rapamycin can also be synthesised by using trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH3CN)2 C12, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
However, the starting material is hard to synthesise, so is usually only the fragment method of synthesis is used for synthetic rapamycin production<br />
<br />
<br />
<font size=5><font color=red>History</font size></font color><br><br />
<br><br />
Rapamycin is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a [http://en.wikipedia.org/wiki/Polyketide ''Polyketide''] pathway. The polyketide chain is formed by condensation of seven [http://en.wikipedia.org/wiki/Acetate''acetate''] components and same number of [http://en.wikipedia.org/wiki/Propionate''propionate''] units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br><br />
6) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato; J. Am. Chem. Soc.; 115; 1993; 4419-4420 <br><br />
7) D. Romo, D. D. Johnson, L. Plamondon, T. Miwa, S. L. Schreiber; J. Org. Chem.; 57; 1992; 5060-5063</div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=4012
It:Rapamycin
2006-10-24T17:09:34Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:rapa2d.JPG|200|2D structure of Rapamycin|200|2D structure of Rapamycin]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
Rapamycin is the type of macrolides that do not obtain sugar moieties, which is that there is a sub group in the presence of an amino acid within the macrocyclic ring; therefore it has both an ester and an amide bond in the ring.<br />
<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
<br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin can be synthesised in many different ways.<br />
One synthesis route is to use trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH3CN)2 C12, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
<br />
<br />
<font size=5><font color=red>History</font size></font color><br><br />
<br><br />
Rapamycin is a 31-memebered macrolide which is first isolated in 1975. The property of that its potent immunosuppressive and antiumour activities were first discovered in 1977. The studies of the prevention of organ rejection after transplant surgery, and phase III clinical trials were completed in 1999.<br />
<br />
X-ray crystallography determined the solid state structure of rapamycin in 1978, followed by degradation studies in 1980 and correct NMR published in 1991. <br />
The solution-phase structure was confirmed using molecular modelling calculations.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>Biosynthesis--the formation of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin having the isotope-labelled is produced via a polyketide pathway. The polyketide chain is formed by condensation of seven acetate components and same number of propionate units. The cyclohexyl starter units produced that derived from shikimc acid then via a dihydroxycyclohexanecarboxylic intermediate. The pipecolate moiety is formed from free pipecolic acid which is made by cyclodeamination of lysine. To achieve the rapamycin also demands O-methylations by S-adenosylmethionine-dependent methyltranferases and oxidations which having cytochrome-p450 mono-oxgenases as catalysts.<br><br />
<br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br></div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=3962
It:Rapamycin
2006-10-24T16:11:14Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:rapa2d.JPG|200|2D structure of Rapamycin|200|2D structure of Rapamycin]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin can be synthesised in many different ways.<br />
One synthesis route is to use trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH3CN)2 C12, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
<br><br><br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT 5)http://www.pubmedcentral.gov/picrender.fcgi?artid=1169993&blobtype=pdf<br></div>
Qlw05
https://chemwiki.ch.ic.ac.uk/index.php?title=It:Rapamycin&diff=3961
It:Rapamycin
2006-10-24T16:09:15Z
<p>Qlw05: </p>
<hr />
<div>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"<br />
! {{chembox header}} colspan="3" |2D Structure of Rapamycin <br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:rapa2d.JPG|200|2D structure of Rapamycin|200|2D structure of Rapamycin]] <br />
|-<br />
! {{chembox header}} colspan="3" |3D structure of Rapamycin<br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" | <jmol><br />
<jmolApplet><br />
<size>200</size><br />
<color>white</color><br />
<script>zoom 100; cpk off;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1;</script><br />
<inlineContents>HEADER NONAME 20-Oct-06 NONE 1<br />
TITLE NONE 2<br />
AUTHOR WWW daemon apache NONE 3<br />
REVDAT 1 20-Oct-06 0 NONE 4<br />
ATOM 1 C 0 8.027 -2.746 -4.135 0.00 0.00 C+0<br />
ATOM 2 C 0 7.216 -2.718 -2.837 0.00 0.00 C+0<br />
ATOM 3 H 0 7.321 -3.673 -2.322 0.00 0.00 H+0<br />
ATOM 4 C 0 5.742 -2.472 -3.162 0.00 0.00 C+0<br />
ATOM 5 C 0 4.931 -2.444 -1.865 0.00 0.00 C+0<br />
ATOM 6 C 0 5.449 -1.320 -0.965 0.00 0.00 C+0<br />
ATOM 7 H 0 5.344 -0.365 -1.479 0.00 0.00 H+0<br />
ATOM 8 C 0 4.639 -1.292 0.333 0.00 0.00 C+0<br />
ATOM 9 C 0 3.335 -0.525 0.103 0.00 0.00 C+0<br />
ATOM 10 H 0 3.556 0.438 -0.356 0.00 0.00 H+0<br />
ATOM 11 C 0 2.631 -0.302 1.444 0.00 0.00 C+0<br />
ATOM 12 H 0 1.638 0.111 1.269 0.00 0.00 H+0<br />
ATOM 13 C 0 3.449 0.674 2.294 0.00 0.00 C+0<br />
ATOM 14 C 0 3.608 1.975 1.552 0.00 0.00 C+0<br />
ATOM 15 C 0 4.139 3.193 2.262 0.00 0.00 C+0<br />
ATOM 16 H 0 5.049 3.534 1.768 0.00 0.00 H+0<br />
ATOM 17 C 0 3.105 4.290 2.221 0.00 0.00 C+0<br />
ATOM 18 C 0 2.929 4.986 1.125 0.00 0.00 C+0<br />
ATOM 19 C 0 1.891 6.076 1.084 0.00 0.00 C+0<br />
ATOM 20 H 0 1.797 6.526 2.072 0.00 0.00 H+0<br />
ATOM 21 C 0 0.544 5.485 0.663 0.00 0.00 C+0<br />
ATOM 22 H 0 0.700 4.760 -0.135 0.00 0.00 H+0<br />
ATOM 23 C 0 -0.363 6.585 0.171 0.00 0.00 C+0<br />
ATOM 24 C 0 -1.520 6.258 -0.736 0.00 0.00 C+0<br />
ATOM 25 H 0 -1.874 5.250 -0.524 0.00 0.00 H+0<br />
ATOM 26 C 0 -2.655 7.256 -0.501 0.00 0.00 C+0<br />
ATOM 27 C 0 -3.869 6.866 -1.351 0.00 0.00 C+0<br />
ATOM 28 H 0 -3.539 6.593 -2.353 0.00 0.00 H+0<br />
ATOM 29 C 0 -4.834 8.051 -1.437 0.00 0.00 C+0<br />
ATOM 30 C 0 -4.569 5.694 -0.716 0.00 0.00 C+0<br />
ATOM 31 C 0 -5.039 4.699 -1.461 0.00 0.00 C+0<br />
ATOM 32 C 0 -5.680 3.547 -0.814 0.00 0.00 C+0<br />
ATOM 33 C 0 -5.738 2.362 -1.443 0.00 0.00 C+0<br />
ATOM 34 C 0 -6.260 1.179 -0.765 0.00 0.00 C+0<br />
ATOM 35 C 0 -5.863 -0.027 -1.176 0.00 0.00 C+0<br />
ATOM 36 C 0 -6.343 -1.283 -0.487 0.00 0.00 C+0<br />
ATOM 37 H 0 -5.654 -1.547 0.315 0.00 0.00 H+0<br />
ATOM 38 C 0 -6.393 -2.409 -1.510 0.00 0.00 C+0<br />
ATOM 39 C 0 -5.584 -3.615 -1.052 0.00 0.00 C+0<br />
ATOM 40 H 0 -5.100 -4.072 -1.926 0.00 0.00 H+0<br />
ATOM 41 C 0 -6.509 -4.652 -0.412 0.00 0.00 C+0<br />
ATOM 42 C 0 -5.694 -5.912 -0.091 0.00 0.00 C+0<br />
ATOM 43 C 0 -4.503 -5.493 0.786 0.00 0.00 C+0<br />
ATOM 44 H 0 -4.868 -5.107 1.738 0.00 0.00 H+0<br />
ATOM 45 C 0 -3.596 -6.700 1.033 0.00 0.00 C+0<br />
ATOM 46 C 0 -3.722 -4.398 0.050 0.00 0.00 C+0<br />
ATOM 47 O 0 -3.362 -4.898 -1.247 0.00 0.00 O+0<br />
ATOM 48 O 0 -4.554 -3.254 -0.129 0.00 0.00 O+0<br />
ATOM 49 O 0 -7.648 -1.064 0.055 0.00 0.00 O+0<br />
ATOM 50 C 0 -7.475 -0.784 1.446 0.00 0.00 C+0<br />
ATOM 51 C 0 -4.918 -0.135 -2.344 0.00 0.00 C+0<br />
ATOM 52 C 0 -1.064 6.342 -2.194 0.00 0.00 C+0<br />
ATOM 53 O 0 -0.162 7.728 0.506 0.00 0.00 O+0<br />
ATOM 54 O 0 -0.060 4.837 1.784 0.00 0.00 O+0<br />
ATOM 55 C 0 -0.557 3.581 1.316 0.00 0.00 C+0<br />
ATOM 56 O 0 2.287 7.075 0.141 0.00 0.00 O+0<br />
ATOM 57 C 0 3.770 4.698 -0.093 0.00 0.00 C+0<br />
ATOM 58 C 0 4.450 2.840 3.718 0.00 0.00 C+0<br />
ATOM 59 O 0 3.309 2.041 0.384 0.00 0.00 O+0<br />
ATOM 60 O 0 2.514 -1.566 2.146 0.00 0.00 O+0<br />
ATOM 61 C 0 1.650 -2.503 1.716 0.00 0.00 C+0<br />
ATOM 62 C 0 1.540 -3.803 2.471 0.00 0.00 C+0<br />
ATOM 63 H 0 1.763 -3.606 3.528 0.00 0.00 H+0<br />
ATOM 64 C 0 0.145 -4.393 2.344 0.00 0.00 C+0<br />
ATOM 65 N 0 -0.076 -4.877 0.987 0.00 0.00 N+0<br />
ATOM 66 C 0 -1.182 -4.622 0.288 0.00 0.00 C+0<br />
ATOM 67 C 0 -2.462 -4.084 0.810 0.00 0.00 C+0<br />
ATOM 68 O 0 -2.490 -3.413 1.814 0.00 0.00 O+0<br />
ATOM 69 O 0 -1.137 -4.858 -0.902 0.00 0.00 O+0<br />
ATOM 70 C 0 0.938 -5.754 0.364 0.00 0.00 C+0<br />
ATOM 71 C 0 2.303 -5.066 0.463 0.00 0.00 C+0<br />
ATOM 72 C 0 2.582 -4.793 1.944 0.00 0.00 C+0<br />
ATOM 73 O 0 0.971 -2.305 0.736 0.00 0.00 O+0<br />
ATOM 74 C 0 2.424 -1.334 -0.822 0.00 0.00 C+0<br />
ATOM 75 C 0 6.924 -1.566 -0.639 0.00 0.00 C+0<br />
ATOM 76 C 0 7.734 -1.594 -1.937 0.00 0.00 C+0<br />
ATOM 77 H 0 7.629 -0.639 -2.451 0.00 0.00 H+0<br />
ATOM 78 O 0 9.111 -1.823 -1.633 0.00 0.00 O+0<br />
ATOM 79 C 0 9.713 -0.540 -1.448 0.00 0.00 C+0<br />
ATOM 80 H 0 7.922 -1.791 -4.649 0.00 0.00 H+0<br />
ATOM 81 H 0 9.077 -2.921 -3.903 0.00 0.00 H+0<br />
ATOM 82 H 0 7.658 -3.547 -4.776 0.00 0.00 H+0<br />
ATOM 83 H 0 5.637 -1.517 -3.677 0.00 0.00 H+0<br />
ATOM 84 H 0 5.373 -3.273 -3.803 0.00 0.00 H+0<br />
ATOM 85 H 0 3.881 -2.269 -2.096 0.00 0.00 H+0<br />
ATOM 86 H 0 5.036 -3.399 -1.350 0.00 0.00 H+0<br />
ATOM 87 H 0 4.411 -2.312 0.641 0.00 0.00 H+0<br />
ATOM 88 H 0 5.218 -0.798 1.113 0.00 0.00 H+0<br />
ATOM 89 H 0 2.933 0.855 3.237 0.00 0.00 H+0<br />
ATOM 90 H 0 4.432 0.247 2.493 0.00 0.00 H+0<br />
ATOM 91 H 0 2.512 4.505 3.097 0.00 0.00 H+0<br />
ATOM 92 H 0 -2.933 7.248 0.553 0.00 0.00 H+0<br />
ATOM 93 H 0 -2.323 8.256 -0.780 0.00 0.00 H+0<br />
ATOM 94 H 0 -4.326 8.900 -1.895 0.00 0.00 H+0<br />
ATOM 95 H 0 -5.697 7.774 -2.041 0.00 0.00 H+0<br />
ATOM 96 H 0 -5.164 8.324 -0.435 0.00 0.00 H+0<br />
ATOM 97 H 0 -4.685 5.661 0.359 0.00 0.00 H+0<br />
ATOM 98 H 0 -4.958 4.739 -2.535 0.00 0.00 H+0<br />
ATOM 99 H 0 -6.116 3.662 0.168 0.00 0.00 H+0<br />
ATOM 100 H 0 -5.409 2.280 -2.473 0.00 0.00 H+0<br />
ATOM 101 H 0 -6.962 1.272 0.047 0.00 0.00 H+0<br />
ATOM 102 H 0 -7.430 -2.711 -1.657 0.00 0.00 H+0<br />
ATOM 103 H 0 -5.991 -2.049 -2.457 0.00 0.00 H+0<br />
ATOM 104 H 0 -6.932 -4.246 0.508 0.00 0.00 H+0<br />
ATOM 105 H 0 -7.312 -4.902 -1.105 0.00 0.00 H+0<br />
ATOM 106 H 0 -6.316 -6.626 0.448 0.00 0.00 H+0<br />
ATOM 107 H 0 -5.330 -6.360 -1.016 0.00 0.00 H+0<br />
ATOM 108 H 0 -3.227 -7.079 0.080 0.00 0.00 H+0<br />
ATOM 109 H 0 -2.754 -6.400 1.656 0.00 0.00 H+0<br />
ATOM 110 H 0 -4.162 -7.482 1.540 0.00 0.00 H+0<br />
ATOM 111 H 0 -2.872 -4.193 -1.692 0.00 0.00 H+0<br />
ATOM 112 H 0 -6.892 0.129 1.562 0.00 0.00 H+0<br />
ATOM 113 H 0 -8.451 -0.653 1.914 0.00 0.00 H+0<br />
ATOM 114 H 0 -6.952 -1.613 1.922 0.00 0.00 H+0<br />
ATOM 115 H 0 -4.220 0.701 -2.325 0.00 0.00 H+0<br />
ATOM 116 H 0 -4.364 -1.072 -2.277 0.00 0.00 H+0<br />
ATOM 117 H 0 -5.486 -0.114 -3.274 0.00 0.00 H+0<br />
ATOM 118 H 0 -0.257 5.629 -2.363 0.00 0.00 H+0<br />
ATOM 119 H 0 -1.901 6.106 -2.851 0.00 0.00 H+0<br />
ATOM 120 H 0 -0.708 7.350 -2.406 0.00 0.00 H+0<br />
ATOM 121 H 0 -1.241 3.749 0.483 0.00 0.00 H+0<br />
ATOM 122 H 0 0.276 2.962 0.983 0.00 0.00 H+0<br />
ATOM 123 H 0 -1.086 3.076 2.123 0.00 0.00 H+0<br />
ATOM 124 H 0 3.137 7.422 0.443 0.00 0.00 H+0<br />
ATOM 125 H 0 4.462 3.885 0.127 0.00 0.00 H+0<br />
ATOM 126 H 0 3.123 4.410 -0.922 0.00 0.00 H+0<br />
ATOM 127 H 0 4.333 5.591 -0.365 0.00 0.00 H+0<br />
ATOM 128 H 0 5.198 2.048 3.747 0.00 0.00 H+0<br />
ATOM 129 H 0 4.833 3.721 4.231 0.00 0.00 H+0<br />
ATOM 130 H 0 3.539 2.499 4.211 0.00 0.00 H+0<br />
ATOM 131 H 0 0.039 -5.222 3.045 0.00 0.00 H+0<br />
ATOM 132 H 0 -0.593 -3.627 2.579 0.00 0.00 H+0<br />
ATOM 133 H 0 0.970 -6.709 0.888 0.00 0.00 H+0<br />
ATOM 134 H 0 0.686 -5.918 -0.684 0.00 0.00 H+0<br />
ATOM 135 H 0 3.076 -5.718 0.056 0.00 0.00 H+0<br />
ATOM 136 H 0 2.284 -4.126 -0.089 0.00 0.00 H+0<br />
ATOM 137 H 0 3.579 -4.367 2.056 0.00 0.00 H+0<br />
ATOM 138 H 0 2.516 -5.725 2.506 0.00 0.00 H+0<br />
ATOM 139 H 0 1.388 -1.033 -0.667 0.00 0.00 H+0<br />
ATOM 140 H 0 2.704 -1.150 -1.859 0.00 0.00 H+0<br />
ATOM 141 H 0 2.530 -2.396 -0.600 0.00 0.00 H+0<br />
ATOM 142 H 0 7.292 -0.765 0.002 0.00 0.00 H+0<br />
ATOM 143 H 0 7.028 -2.521 -0.125 0.00 0.00 H+0<br />
ATOM 144 H 0 10.770 -0.665 -1.213 0.00 0.00 H+0<br />
ATOM 145 H 0 9.610 0.044 -2.362 0.00 0.00 H+0<br />
ATOM 146 H 0 9.217 -0.022 -0.628 0.00 0.00 H+0<br />
CONECT 1 2 80 81 82 NONE 151<br />
CONECT 2 1 3 76 4 NONE 152<br />
CONECT 4 2 5 83 84 NONE 153<br />
CONECT 5 4 6 85 86 NONE 154<br />
CONECT 6 5 7 8 75 NONE 155<br />
CONECT 8 6 9 87 88 NONE 156<br />
CONECT 9 8 10 11 74 NONE 157<br />
CONECT 11 9 12 13 60 NONE 158<br />
CONECT 13 11 14 89 90 NONE 159<br />
CONECT 14 13 15 59 0 NONE 160<br />
CONECT 15 14 16 17 58 NONE 161<br />
CONECT 17 15 18 91 0 NONE 162<br />
CONECT 18 17 19 57 0 NONE 163<br />
CONECT 19 18 20 21 56 NONE 164<br />
CONECT 21 19 22 23 54 NONE 165<br />
CONECT 23 21 24 53 0 NONE 166<br />
CONECT 24 23 25 26 52 NONE 167<br />
CONECT 26 24 27 92 93 NONE 168<br />
CONECT 27 26 28 29 30 NONE 169<br />
CONECT 29 27 94 95 96 NONE 170<br />
CONECT 30 27 31 97 0 NONE 171<br />
CONECT 31 30 32 98 0 NONE 172<br />
CONECT 32 31 33 99 0 NONE 173<br />
CONECT 33 32 34 100 0 NONE 174<br />
CONECT 34 33 35 101 0 NONE 175<br />
CONECT 35 34 36 51 0 NONE 176<br />
CONECT 36 35 37 38 49 NONE 177<br />
CONECT 38 36 39 102 103 NONE 178<br />
CONECT 39 38 40 48 41 NONE 179<br />
CONECT 41 39 42 104 105 NONE 180<br />
CONECT 42 41 43 106 107 NONE 181<br />
CONECT 43 42 44 45 46 NONE 182<br />
CONECT 45 43 108 109 110 NONE 183<br />
CONECT 46 43 47 67 48 NONE 184<br />
CONECT 47 46 111 0 0 NONE 185<br />
CONECT 48 46 39 0 0 NONE 186<br />
CONECT 49 36 50 0 0 NONE 187<br />
CONECT 50 49 112 113 114 NONE 188<br />
CONECT 51 35 115 116 117 NONE 189<br />
CONECT 52 24 118 119 120 NONE 190<br />
CONECT 53 23 0 0 0 NONE 191<br />
CONECT 54 21 55 0 0 NONE 192<br />
CONECT 55 54 121 122 123 NONE 193<br />
CONECT 56 19 124 0 0 NONE 194<br />
CONECT 57 18 125 126 127 NONE 195<br />
CONECT 58 15 128 129 130 NONE 196<br />
CONECT 59 14 0 0 0 NONE 197<br />
CONECT 60 11 61 0 0 NONE 198<br />
CONECT 61 60 62 73 0 NONE 199<br />
CONECT 62 61 63 72 64 NONE 200<br />
CONECT 64 62 65 131 132 NONE 201<br />
CONECT 65 64 66 70 0 NONE 202<br />
CONECT 66 65 67 69 0 NONE 203<br />
CONECT 67 66 46 68 0 NONE 204<br />
CONECT 68 67 0 0 0 NONE 205<br />
CONECT 69 66 0 0 0 NONE 206<br />
CONECT 70 65 71 133 134 NONE 207<br />
CONECT 71 70 72 135 136 NONE 208<br />
CONECT 72 71 62 137 138 NONE 209<br />
CONECT 73 61 0 0 0 NONE 210<br />
CONECT 74 9 139 140 141 NONE 211<br />
CONECT 75 6 76 142 143 NONE 212<br />
CONECT 76 75 77 2 78 NONE 213<br />
CONECT 78 76 79 0 0 NONE 214<br />
CONECT 79 78 144 145 146 NONE 215<br />
END <br />
</inlineContents><br />
</jmolApplet><br />
</jmol><br />
|-<br />
| align="center" colspan="3" bgcolor="#ffffff" |<br />
|- <br />
! {{chembox header}} colspan="3"| Properties<br />
|-<br />
| CA Index Name<br />
| colspan="2"| Rapamycin- (9CI)<br />
|- <br />
| Other Names<br />
|colspan="2"| Sirolimus<br />
<br />
Rapamune<br />
<br />
AY-22989<br />
<br />
RAPA<br />
<br />
NSC-226080<br />
|-<br />
| Chemical formula|Molecular formula<br />
| colspan="2" | C<sub>51</sub>H<sub>79</sub>N<sub></sub>O<sub>13 <br />
|-<br />
| Molar mass<br />
| colspan="2" | 914.17 g/mol<br />
|-<br />
| CAS registry number|CAS number<br />
| colspan="2" | 53123-88-9<br />
|-<br />
| Appearance<br />
| colspan="2" | White to off-white solid<br />
|-<br />
| Melting point<br />
| colspan="2" | 183-185 °C<br />
|-<br />
| pKa<br />
| colspan="2" | ~10.4<br />
|}<br />
<br />
<br />
'''Rapamycin''' also known as Sirolimus, is a potent immunosuppressive and anti-proliferative natural product isolated from the bacteria strain ''Streptomyces hygroscopicus''. It is used as a drug to help prevent the body from rejecting organ and bone marrow transplants and also being studied as a treatment for cancer.<br />
<br />
<br><br><br />
<font size=5><font color=red>How does Rapamycin work?</font size></font color><br><br />
<br><br />
Rapamycin potently inhibits downstream signaling from the mammalian target of rapamycin (mTOR) proteins which functions in a signaling pathway to promote tumor growth<sup>2</sup>. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. Rapamycin binds to the FK-506 binding protein and the rapamycin/FKBP12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway.<br> <br />
<br />
Rapamycin selectively inhibits the phosphorylation and activation of p70 S6 kinase<sup>3</sup>. It prevents the translational activation of IGF-II and inhibits later signaling events such as p110Rb phosphorylation and cyclin A synthesis. <br><br />
<br />
<font size=5><font color=red>Side Effects taking of Rapamycin</font size></font color><br><br />
<br><br />
While taking Rapamycin, there are certain side effects that occur in the body. <br />
Some of the side effects may take place after many years of taking the medicine. These delayed effects, can also include certain cancers, such as lymphoma, though these are extreme cases. <br />
<br />
Common side effects include chest pains, abdominal pain, fever, muscle pains or cramps, nausea, mood changes, tiredness and weakness. <br />
Less common side effects include, skin ulcers, nose bleeds and in rare cases weight gain may also occur. <sup>4</sup> <br />
<br />
<font size=5><font color=red>Synthesis of Rapamycin</font size></font color><br><br />
<br><br />
Rapamycin can be synthesised in many different ways.<br />
One synthesis route is to use trans-1,2-Bis(tri-n-butylstannyl)ethylen reacting with the reagants diisopropylethylamine and Pd(CH3CN)2 C12, using dimethylformide, and tetrahydrofuran as the solvents.<br />
<br />
[[Image:synthesis.JPG]] <br />
<br />
<br><br><br />
<font size=5><font color=red>How does rapamycin work in mammalian cells?</font size></font color><br><br />
<br><br />
The bacterial macrolide--immunosuppressant rapamycin in the mammalian cells suppresses mitogen-induced translation of mRNAs selectively, which is the most notably mRNAs encoding ribosomal proteins and elongation factors. In a mean time, rapamycin also blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorlation and activation.<br><br />
<br />
<br />
<font size=5><font color=red>References</font size></font color><br> <br />
<br><br />
<br />
1) [http://www.proteinkinase.biz/html/protein_kinase_inhibitors.html © Biaffin GmbH & Co KG, Protein kinase inhibitors]<br><br />
2) Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase" Nature 358(6381):70-3<br><br />
3) Kahan BD, Murgia MG, Slaton J, et al. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit. 1995;17:672-675. <br><br />
4) http://www.healthtouch.com/bin/EContent_HT/drugShowLfts.asp?fname=usp0790.htm&title=Rapamycin&cid=HT <br></div>
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