5njh
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Triazolopyrimidines stabilize microtubules by binding to the vinca inhibitor site of tubulin== | |
| + | <StructureSection load='5njh' size='340' side='right' caption='[[5njh]], [[Resolution|resolution]] 2.39Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5njh]] 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=5NJH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NJH FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8Z8:5-chloranyl-7-[(1~{R},5~{S})-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl]-6-[2,4,6-tris(fluoranyl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine'>8Z8</scene>, <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=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=5njh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5njh OCA], [http://pdbe.org/5njh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5njh RCSB], [http://www.ebi.ac.uk/pdbsum/5njh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5njh 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 == | ||
| + | Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells. | ||
| - | + | Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin.,Saez-Calvo G, Sharma A, Balaguer FA, Barasoain I, Rodriguez-Salarichs J, Olieric N, Munoz-Hernandez H, Berbis MA, Wendeborn S, Penalva MA, Matesanz R, Canales A, Prota AE, Jimenez-Barbero J, Andreu JM, Lamberth C, Steinmetz MO, Diaz JF Cell Chem Biol. 2017 Jun 22;24(6):737-750.e6. doi:, 10.1016/j.chembiol.2017.05.016. Epub 2017 Jun 1. PMID:28579361<ref>PMID:28579361</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5njh" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Bos taurus]] | ||
| + | [[Category: Buffalo rat]] | ||
| + | [[Category: Chick]] | ||
| + | [[Category: Calvo, G S]] | ||
| + | [[Category: Diaz, J F]] | ||
| + | [[Category: Prota, A E]] | ||
| + | [[Category: Sharma, A]] | ||
| + | [[Category: Steinmetz, M O]] | ||
| + | [[Category: Antitumoural]] | ||
| + | [[Category: Microtubule targeting agent]] | ||
| + | [[Category: Microtubule]] | ||
| + | [[Category: Resistance to chemotherapy]] | ||
| + | [[Category: Structural protein]] | ||
| + | [[Category: Tubulin]] | ||
Revision as of 08:12, 16 November 2017
Triazolopyrimidines stabilize microtubules by binding to the vinca inhibitor site of tubulin
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