4o2a

Tubulin-BAL27862 complex

spinqualitylabelsall models 4o2a, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4o2a is a 6 chain structure with sequence from Bos taurus, Buffalo rat and Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2RR, ADP, CA, CL, GDP, GOL, GTP, IMD, MES, MG Related: 4o2b Gene: Stmn4 (Buffalo rat), TTL (CHICK) 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 Microtubule-targeting agents are widely used for the treatment of cancer and as tool compounds to study the microtubule cytoskeleton. BAL27862 is a novel microtubule-destabilizing drug that is currently undergoing phase I clinical evaluation as the prodrug BAL101553. The drug is a potent inhibitor of tumor cell growth and shows a promising activity profile in a panel of human cancer models resistant to clinically relevant microtubule-targeting agents. Here, we evaluated the molecular mechanism of the tubulin-BAL27862 interaction using a combination of cell biology, biochemistry and structural biology methods. Tubulin-binding assays revealed that BAL27862 potently inhibited tubulin assembly at 37 degrees C with an IC50 of 1.4muM and bound to unassembled tubulin with a stoichiometry of 1mol/mol tubulin and a dissociation constant of 244+/-30nM. BAL27862 bound to tubulin independently of vinblastine, without the formation of tubulin oligomers. The kinetics of BAL27862 binding to tubulin were distinct from those of colchicine, with evidence of competition between BAL27862 and colchicine for binding. Determination of the tubulin-BAL27862 structure by X-ray crystallography demonstrated that BAL27862 binds to the same site as colchicine at the intradimer interface. Comparison of crystal structures of tubulin-BAL27862 and tubulin-colchicine complexes shows that the binding mode of BAL27862 to tubulin is similar to that of colchicine. However, comparative analyses of the effects of BAL27862 and colchicine on the microtubule mitotic spindle and in tubulin protease-protection experiments suggest different outcomes of tubulin binding. Taken together, our data define BAL27862 as a potent, colchicine site-binding, microtubule-destabilizing agent with distinct effects on microtubule organization. The Novel Microtubule-Destabilizing Drug BAL27862 Binds to the Colchicine Site of Tubulin with Distinct Effects on Microtubule Organization.,Prota AE, Danel F, Bachmann F, Bargsten K, Buey RM, Pohlmann J, Reinelt S, Lane H, Steinmetz MO J Mol Biol. 2014 Apr 17;426(8):1848-60. doi: 10.1016/j.jmb.2014.02.005. Epub 2014, Feb 11. PMID:24530796 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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