6fkl: Difference between revisions
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==Tubulin-TUB015 complex== | |||
<StructureSection load='6fkl' size='340' side='right' caption='[[6fkl]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6fkl]] 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=6FKL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FKL FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DLK:2-{1-[(2-Methoxyphenyl)amino]ethylidene}-5-phenyl-1,3-cyclohexanedione'>DLK</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fkj|6fkj]]</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=6fkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fkl OCA], [http://pdbe.org/6fkl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fkl RCSB], [http://www.ebi.ac.uk/pdbsum/6fkl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fkl ProSAT]</span></td></tr> | |||
</table> | |||
== 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). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub muM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K b value of 2.87 x 10(8) M(-1) which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand. | |||
High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.,Bueno O, Estevez Gallego J, Martins S, Prota AE, Gago F, Gomez-SanJuan A, Camarasa MJ, Barasoain I, Steinmetz MO, Diaz JF, Perez-Perez MJ, Liekens S, Priego EM Sci Rep. 2018 Mar 9;8(1):4242. doi: 10.1038/s41598-018-22382-x. PMID:29523799<ref>PMID:29523799</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6fkl" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Priego, E M]] | |||
[[Category: Prota, A E]] | |||
[[Category: Steinmetz, M O]] | |||
[[Category: Cell cycle]] | |||
[[Category: Cytoskeleton]] | |||
[[Category: Microtubule]] | |||
[[Category: Tubulin fold]] | |||
Latest revision as of 10:44, 21 March 2018
Tubulin-TUB015 complexTubulin-TUB015 complex
Structural highlights
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 PubMedMicrotubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub muM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K b value of 2.87 x 10(8) M(-1) which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand. High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.,Bueno O, Estevez Gallego J, Martins S, Prota AE, Gago F, Gomez-SanJuan A, Camarasa MJ, Barasoain I, Steinmetz MO, Diaz JF, Perez-Perez MJ, Liekens S, Priego EM Sci Rep. 2018 Mar 9;8(1):4242. doi: 10.1038/s41598-018-22382-x. PMID:29523799[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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