View source for 6qqn


==Tubulin-TH588 complex==
<StructureSection load='6qqn' size='340' side='right'caption='[[6qqn]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qqn]] 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=6QQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QQN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.301&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2GE:N~4~-CYCLOPROPYL-6-(2,3-DICHLOROPHENYL)PYRIMIDINE-2,4-DIAMINE'>2GE</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=6qqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qqn OCA], [https://pdbe.org/6qqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qqn RCSB], [https://www.ebi.ac.uk/pdbsum/6qqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qqn ProSAT]</span></td></tr>
</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 ==
There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to beta-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.

VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells.,Patterson JC, Joughin BA, Prota AE, Muhlethaler T, Jonas OH, Whitman MA, Varmeh S, Chen S, Balk SP, Steinmetz MO, Lauffenburger DA, Yaffe MB Cell Syst. 2019 Jul 10. pii: S2405-4712(19)30190-5. doi:, 10.1016/j.cels.2019.05.009. PMID:31302152<ref>PMID:31302152</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qqn" 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__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Balk SP]]
[[Category: Chen S]]
[[Category: Jonas OH]]
[[Category: Joughin BA]]
[[Category: Lauffenburger DA]]
[[Category: Muehlethaler T]]
[[Category: Patterson JC]]
[[Category: Prota AE]]
[[Category: Steinmetz MO]]
[[Category: Varmeh S]]
[[Category: Whitman MA]]
[[Category: Yaffe MB]]