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6qqn

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Revision as of 06:23, 7 August 2019

Tubulin-TH588 complex

Structural highlights

6qqn is a 6 chain structure with sequence from Bos taurus, Buffalo rat and Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , , ,
Gene:	Stmn4 (Buffalo rat), TTL (CHICK)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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. [STMN4_RAT] Exhibits microtubule-destabilizing activity.^[1] ^[2] ^[3] [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).

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nakao C, Itoh TJ, Hotani H, Mori N. Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain. J Biol Chem. 2004 May 28;279(22):23014-21. Epub 2004 Mar 22. PMID:15039434 doi:http://dx.doi.org/10.1074/jbc.M313693200
↑ Gavet O, El Messari S, Ozon S, Sobel A. Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons. J Neurosci Res. 2002 Jun 1;68(5):535-50. PMID:12111843 doi:http://dx.doi.org/10.1002/jnr.10234
↑ Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004 Mar 11;428(6979):198-202. PMID:15014504 doi:http://dx.doi.org/10.1038/nature02393
↑ Patterson JC, Joughin BA, Prota AE, Muhlethaler T, Jonas OH, Whitman MA, Varmeh S, Chen S, Balk SP, Steinmetz MO, Lauffenburger DA, Yaffe MB. VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells. Cell Syst. 2019 Jul 10. pii: S2405-4712(19)30190-5. doi:, 10.1016/j.cels.2019.05.009. PMID:31302152 doi:http://dx.doi.org/10.1016/j.cels.2019.05.009

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6qqn"

@@ Line 3: / Line 3: @@
 <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 [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QQN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6qqn]] 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=6QQN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QQN FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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=6qqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qqn OCA], [http://pdbe.org/6qqn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qqn RCSB], [http://www.ebi.ac.uk/pdbsum/6qqn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qqn ProSAT]</span></td></tr>
 </table>
@@ Line 23: / Line 24: @@
 </StructureSection>
 [[Category: Bos taurus]]
+[[Category: Buffalo rat]]
+[[Category: Chick]]
 [[Category: Large Structures]]
 [[Category: Balk, S P]]

6qqn

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Revision as of 06:23, 7 August 2019

Tubulin-TH588 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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