5mf4
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==Tubulin-Dictyostatin complex== | ==Tubulin-Dictyostatin complex== | ||
| - | <StructureSection load='5mf4' size='340' side='right' caption='[[5mf4]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='5mf4' size='340' side='right'caption='[[5mf4]], [[Resolution|resolution]] 2.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5mf4]] is a 6 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[5mf4]] 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=5MF4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MF4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7LZ:(3~{Z},5~{E},7~{R},8~{S},10~{S},11~{Z},13~{S},14~{R},15~{S},17~{S},20~{R},21~{S},22~{S})-22-[(2~{S},3~{Z})-hexa-3,5-dien-2-yl]-7,13,15,17,21-pentamethyl-8,10,14,20-tetrakis(oxidanyl)-1-oxacyclodocosa-3,5,11-trien-2-one'>7LZ</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7LZ:(3~{Z},5~{E},7~{R},8~{S},10~{S},11~{Z},13~{S},14~{R},15~{S},17~{S},20~{R},21~{S},22~{S})-22-[(2~{S},3~{Z})-hexa-3,5-dien-2-yl]-7,13,15,17,21-pentamethyl-8,10,14,20-tetrakis(oxidanyl)-1-oxacyclodocosa-3,5,11-trien-2-one'>7LZ</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=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=5mf4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mf4 OCA], [https://pdbe.org/5mf4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mf4 RCSB], [https://www.ebi.ac.uk/pdbsum/5mf4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mf4 ProSAT]</span></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</table> | </table> | ||
== Function == | == 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 == | ||
| + | A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin-dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure-activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents. | ||
| + | |||
| + | Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells.,Trigili C, Barasoain I, Sanchez-Murcia PA, Bargsten K, Redondo-Horcajo M, Nogales A, Gardner NM, Meyer A, Naylor GJ, Gomez-Rubio E, Gago F, Steinmetz MO, Paterson I, Prota AE, Diaz JF ACS Omega. 2016 Dec 31;1(6):1192-1204. doi: 10.1021/acsomega.6b00317. Epub 2016, Dec 13. PMID:30023505<ref>PMID:30023505</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5mf4" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Stathmin-4 3D structures|Stathmin-4 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
| - | [[Category: | + | [[Category: Gallus gallus]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: Barasoain | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Bargsten | + | [[Category: Barasoain I]] |
| - | [[Category: Diaz | + | [[Category: Bargsten K]] |
| - | [[Category: Gago | + | [[Category: Diaz JF]] |
| - | [[Category: Gardner | + | [[Category: Gago F]] |
| - | [[Category: Gomez-Rubio | + | [[Category: Gardner NM]] |
| - | [[Category: Meyer | + | [[Category: Gomez-Rubio E]] |
| - | [[Category: Naylor | + | [[Category: Meyer A]] |
| - | [[Category: Nogales | + | [[Category: Naylor GJ]] |
| - | [[Category: Paterson | + | [[Category: Nogales A]] |
| - | [[Category: Prota | + | [[Category: Paterson I]] |
| - | [[Category: Redondo-Horcajo | + | [[Category: Prota AE]] |
| - | [[Category: Sanchez-Murcia | + | [[Category: Redondo-Horcajo M]] |
| - | [[Category: Steinmetz | + | [[Category: Sanchez-Murcia PA]] |
| - | [[Category: Trigili | + | [[Category: Steinmetz MO]] |
| - | + | [[Category: Trigili C]] | |
| - | + | ||
| - | + | ||
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Current revision
Tubulin-Dictyostatin complex
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Categories: Bos taurus | Gallus gallus | Large Structures | Rattus norvegicus | Barasoain I | Bargsten K | Diaz JF | Gago F | Gardner NM | Gomez-Rubio E | Meyer A | Naylor GJ | Nogales A | Paterson I | Prota AE | Redondo-Horcajo M | Sanchez-Murcia PA | Steinmetz MO | Trigili C
