5j2t
From Proteopedia
Tubulin-vinblastine complex
Structural highlights
FunctionTBA1B_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. Publication Abstract from PubMedThe auristatin class of microtubule destabilizers are highly potent cytotoxic agents against several cancer cell types when delivered as antibody drug conjugates. Here we describe the high resolution structures of tubulin in complex with both monomethyl auristatin E and F and unambiguously define the trans-configuration of both ligands at the Val-Dil amide bond in their tubulin bound state. Moreover, we illustrate how peptidic vinca-site agents carrying terminal carboxylate residues may exploit an observed extended hydrogen bond network with the M-loop Arg278 to greatly improve the affinity of the corresponding analogs and to maintain the M-loop in an incompatible conformation for productive lateral tubulin-tubulin contacts in microtubules. Our results highlight a potential, previously undescribed molecular mechanism by which peptidic vinca-site agents maintain unparalleled potency as microtubule-destabilizing agents. Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics.,Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE PLoS One. 2016 Aug 12;11(8):e0160890. doi: 10.1371/journal.pone.0160890., eCollection 2016. PMID:27518442[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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