5m7e | pdb_00005m7e

Tubulin-BKM120 complex

spinqualitylabelsall models 5m7e, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5m7e is a 6 chain structure with sequence from [1] and Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACP, CA, GDP, GOL, GTP, MES, MG, SD5 Related: 4o2b 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. [STMN4_RAT] Exhibits microtubule-destabilizing activity. [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 PubMed BKM120 (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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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