4tv8

Tubulin-Maytansine complex

spinqualitylabelsall models 4tv8, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tv8 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: 3GT, ACP, CA, GDP, GOL, GTP, MES, MG Related: 4tv9 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 The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on beta-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer. A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.,Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, Neuhaus C, Andreu JM, Altmann KH, Steinmetz MO Proc Natl Acad Sci U S A. 2014 Aug 11. pii: 201408124. PMID:25114240 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Stathmin Tubulin Tubulin tyrosine ligase

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