7z2p: Difference between revisions
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==== | ==Tubulin-nocodazole complex== | ||
<StructureSection load='7z2p' size='340' side='right'caption='[[7z2p]]' scene=''> | <StructureSection load='7z2p' size='340' side='right'caption='[[7z2p]], [[Resolution|resolution]] 2.00Å' 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'>[[7z2p]] 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=7Z2P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z2P 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=7z2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z2p OCA], [https://pdbe.org/7z2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z2p RCSB], [https://www.ebi.ac.uk/pdbsum/7z2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z2p ProSAT]</span></td></tr> | </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=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>, <scene name='pdbligand=NW6:nocodazole'>NW6</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=7z2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z2p OCA], [https://pdbe.org/7z2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z2p RCSB], [https://www.ebi.ac.uk/pdbsum/7z2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z2p 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 == | |||
Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-binding fragments can indeed be used as valuable starting points for the development of active, lead-like antitubulin small molecules. To this end, we report on a new, rationally designed series of 2-aminobenzimidazole derivatives that destabilize MTs by binding tubulin at the colchicine-binding site (CBS). We applied a fragment growing strategy by combining X-ray crystallography and computer-aided drug design. Preliminary structure-activity-relationship studies afforded compound 18 that inhibits HeLa cell viability with a submicromolar activity (IC50 of 0.9 muM). X-ray crystallography confirmed the compound pose in the CBS, while immunostaining experiments suggested a molecular mechanism of action alike classical CBS ligands with antimitotic and antitumor activity associated with MTs destabilization. This promising outcome underpins that our previously performed combined computational and crystallographic fragment screening approach provides promising starting points for developing new MTAs binding to the CBS of tubulin and, eventually, to further tubulin pockets. | |||
Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents.,de la Roche NM, Muhlethaler T, Di Martino RMC, Ortega JA, Gioia D, Roy B, Prota AE, Steinmetz MO, Cavalli A Eur J Med Chem. 2022 Nov 5;241:114614. doi: 10.1016/j.ejmech.2022.114614. Epub, 2022 Jul 16. PMID:35939994<ref>PMID:35939994</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7z2p" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | |||
[[Category: Gallus gallus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: Cavalli A]] | |||
[[Category: Muehlethaler T]] | |||
[[Category: Prota AE]] | |||
[[Category: Steinmetz MO]] | |||