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| | <StructureSection load='6ses' size='340' side='right'caption='[[6ses]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='6ses' size='340' side='right'caption='[[6ses]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ses]] 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=6SES OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6SES FirstGlance]. <br> | + | <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='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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</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='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'>[http://proteopedia.org/fgij/fg.htm?mol=6ses FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ses OCA], [http://pdbe.org/6ses PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ses RCSB], [http://www.ebi.ac.uk/pdbsum/6ses PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ses ProSAT]</span></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> | | </table> |
| | == Function == | | == 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). | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6ses" style="background-color:#fffaf0;"></div> | | <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 == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
| - | [[Category: Buffalo rat]] | + | [[Category: Gallus gallus]] |
| - | [[Category: Chick]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Guo, B]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Horwitz, S Band]] | + | [[Category: Band Horwitz S]] |
| - | [[Category: III, A B.Smith]] | + | [[Category: Guo B]] |
| - | [[Category: McDaid, H M]] | + | [[Category: McDaid HM]] |
| - | [[Category: Muehlethaler, T]] | + | [[Category: Muehlethaler T]] |
| - | [[Category: Prota, A E]] | + | [[Category: Prota AE]] |
| - | [[Category: Rodriguez-Gabin, A]] | + | [[Category: Rodriguez-Gabin A]] |
| - | [[Category: Steinmetz, M O]] | + | [[Category: Smith III AB]] |
| - | [[Category: Ye, K]] | + | [[Category: Steinmetz MO]] |
| - | [[Category: Zhang, N]] | + | [[Category: Ye K]] |
| - | [[Category: Cell cycle]] | + | [[Category: Zhang N]] |
| - | [[Category: Cytoskeleton]]
| + | |
| - | [[Category: Microtubule]]
| + | |
| - | [[Category: Tubulin fold]]
| + | |
| Structural highlights
6ses is a 6 chain structure with sequence from Bos taurus, Gallus gallus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2Å |
| Ligands: | , , , , , , |
| 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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Guo B, Rodriguez-Gabin A, Prota A, Muhlethaler T, Zhang N, Ye K, Steinmetz MO, Horwitz SB, Smith AB 3rd, McDaid H. Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence. Mol Pharmacol. 2020 Jun 26. pii: mol.119.117457. doi: 10.1124/mol.119.117457. PMID:32591477 doi:http://dx.doi.org/10.1124/mol.119.117457
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