7e4z: Difference between revisions
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==== | ==Crystal structure of tubulin in complex with Maytansinol== | ||
<StructureSection load='7e4z' size='340' side='right'caption='[[7e4z]]' scene=''> | <StructureSection load='7e4z' size='340' side='right'caption='[[7e4z]], [[Resolution|resolution]] 2.69Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e4z]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E4Z FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e4z OCA], [https://pdbe.org/7e4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e4z RCSB], [https://www.ebi.ac.uk/pdbsum/7e4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e4z ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.69Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=BKL:(1R,2S,3S,5S,6S,16E,18E,20R,21S)-11-chloro-6,21-dihydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1~10,14~.0~3,5~]hexacosa-10(26),11,13,16,18-pentaene-8,23-dione'>BKL</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e4z OCA], [https://pdbe.org/7e4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e4z RCSB], [https://www.ebi.ac.uk/pdbsum/7e4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e4z ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/TBA1B_BOVIN TBA1B_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors. | |||
C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.,Li W, Huang M, Li Y, Xia A, Tan L, Zhang Z, Wang Y, Yang J Biochem Biophys Res Commun. 2021 Aug 20;566:197-203. doi: , 10.1016/j.bbrc.2021.05.071. Epub 2021 Jun 15. PMID:34144258<ref>PMID:34144258</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7e4z" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Stathmin-4 3D structures|Stathmin-4 3D structures]] | |||
*[[Tubulin 3D Structures|Tubulin 3D Structures]] | |||
*[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | |||
[[Category: Gallus gallus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: Li W]] | |||
[[Category: Wang Y]] | |||