View source for 6ses


==Tubulin-B2 complex==
<StructureSection load='6ses' size='340' side='right'caption='[[6ses]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ses]] 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=6SES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SES 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&#8491;</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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=L95:[(3~{Z},5~{S},6~{S},7~{S},8~{R},9~{S},11~{Z},13~{S},14~{S},15~{S},16~{Z},18~{S})-5,7,9,11,13,15-hexamethyl-19-[(2~{S},3~{R})-3-methyl-6-oxidanylidene-oxan-2-yl]-8,14,18-tris(oxidanyl)nonadeca-3,11,16-trien-6-yl]+carbamate'>L95</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=6ses FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ses OCA], [https://pdbe.org/6ses PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ses RCSB], [https://www.ebi.ac.uk/pdbsum/6ses PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ses 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.
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== Publication Abstract from PubMed ==
The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers; malignancies that typically succumb to taxane-resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anti-cancer activity; thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anti-cancer efficacy relative to Taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated (i) improved pharmacologic properties, specifically, increased EMax and AUC, and decreased EC50; (ii) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to Taxol or DDM; (iii) reduced propensity for senescence induction relative to DDM; (iv) superior long-term activity in cancer cells versus Taxol or DDM, and (v) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a high-efficiency DDM congener with broad range anti-cancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anti-cancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and -resistant cancer cell models, diminished risk of chemotherapy-mediated senescence and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to beta-tubulin that could account for the improved anti-cancer activity. These findings support continued pre-clinical development of discodermolide, particularly in the chemorefractory setting.

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence.,Guo B, Rodriguez-Gabin A, Prota A, Muhlethaler T, Zhang N, Ye K, Steinmetz MO, Horwitz SB, Smith AB 3rd, McDaid H Mol Pharmacol. 2020 Jun 26. pii: mol.119.117457. doi: 10.1124/mol.119.117457. PMID:32591477<ref>PMID:32591477</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6ses" 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: Band Horwitz S]]
[[Category: Guo B]]
[[Category: McDaid HM]]
[[Category: Muehlethaler T]]
[[Category: Prota AE]]
[[Category: Rodriguez-Gabin A]]
[[Category: Smith III AB]]
[[Category: Steinmetz MO]]
[[Category: Ye K]]
[[Category: Zhang N]]