5m7e: Difference between revisions
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==Tubulin-BKM120 complex== | ==Tubulin-BKM120 complex== | ||
<StructureSection load='5m7e' size='340' side='right' caption='[[5m7e]], [[Resolution|resolution]] 2.05Å' scene=''> | <StructureSection load='5m7e' size='340' side='right'caption='[[5m7e]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5m7e]] 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=5M7E OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5m7e]] 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=5M7E OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5M7E 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=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>, <scene name='pdbligand=SD5:5-[2,6-DI(MORPHOLIN-4-YL)PYRIMIDIN-4-YL]-4-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE'>SD5</scene></td></tr> | </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=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>, <scene name='pdbligand=SD5:5-[2,6-DI(MORPHOLIN-4-YL)PYRIMIDIN-4-YL]-4-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE'>SD5</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4o2b|4o2b]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4o2b|4o2b]]</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5m7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m7e OCA], [http://pdbe.org/5m7e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m7e RCSB], [http://www.ebi.ac.uk/pdbsum/5m7e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m7e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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==See Also== | ==See Also== | ||
*[[Stathmin|Stathmin]] | *[[Stathmin-4 3D structures|Stathmin-4 3D structures]] | ||
*[[Tubulin 3D Structures|Tubulin 3D Structures]] | |||
*[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]] | |||
*[[User:Alisa Cario|User:Alisa Cario]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Large Structures]] | |||
[[Category: Bohnacker, T]] | [[Category: Bohnacker, T]] | ||
[[Category: Prota, A E]] | [[Category: Prota, A E]] | ||
Revision as of 10:10, 19 August 2020
Tubulin-BKM120 complexTubulin-BKM120 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 PubMedBKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies. Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.,Bohnacker T, Prota AE, Beaufils F, Burke JE, Melone A, Inglis AJ, Rageot D, Sele AM, Cmiljanovic V, Cmiljanovic N, Bargsten K, Aher A, Akhmanova A, Diaz JF, Fabbro D, Zvelebil M, Williams RL, Steinmetz MO, Wymann MP Nat Commun. 2017 Mar 9;8:14683. doi: 10.1038/ncomms14683. PMID:28276440[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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