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6f7c
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==TUBULIN-Compound 12 complex== | |
| + | <StructureSection load='6f7c' size='340' side='right'caption='[[6f7c]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6f7c]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat] and [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F7C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F7C FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CVT:3,4,5-trimethoxy-~{N}-[(~{E})-naphthalen-1-ylmethylideneamino]benzamide'>CVT</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Stmn4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), TTL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 CHICK])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6f7c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f7c OCA], [http://pdbe.org/6f7c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f7c RCSB], [http://www.ebi.ac.uk/pdbsum/6f7c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f7c ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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. [[http://www.uniprot.org/uniprot/STMN4_RAT STMN4_RAT]] Exhibits microtubule-destabilizing activity.<ref>PMID:15039434</ref> <ref>PMID:12111843</ref> <ref>PMID:15014504</ref> [[http://www.uniprot.org/uniprot/TBB2B_BOVIN TBB2B_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 (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters. The crystal structure of the tubulin-bound N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on the T7 loop movement of beta-tubulin, thereby rendering tubulin assembly incompetent. Using dose escalation and short-term repeated dose studies, we further report that this compound class is well tolerated to >100 mg/kg in mice. We finally observed that intraperitoneally administered compound 12 significantly prolonged the overall survival of mice transplanted with both sensitive and multidrug-resistant acute lymphoblastic leukemia (ALL) cells. Taken together, this work describes promising colchicine-site-targeting tubulin inhibitors featuring favorable therapeutic effects against ALL and multidrug-resistant cells. | ||
| - | + | Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia.,Cury NM, Muhlethaler T, Laranjeira ABA, Canevarolo RR, Zenatti PP, Lucena-Agell D, Barasoain I, Song C, Sun D, Dovat S, Yunes RA, Prota AE, Steinmetz MO, Diaz JF, Yunes JA iScience. 2019 Oct 2;21:95-109. doi: 10.1016/j.isci.2019.10.003. PMID:31655259<ref>PMID:31655259</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6f7c" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Bos taurus]] | ||
| + | [[Category: Buffalo rat]] | ||
| + | [[Category: Chick]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Muehlethaler, T]] | ||
| + | [[Category: Prota, A E]] | ||
| + | [[Category: Steinmetz, M O]] | ||
| + | [[Category: Cell cycle]] | ||
| + | [[Category: Cytoskeleton]] | ||
| + | [[Category: Microtubule]] | ||
| + | [[Category: Tubulin fold]] | ||
Current revision
TUBULIN-Compound 12 complex
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