title: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics.
abstract: The 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.
authors: Department of Protein Sciences, Seattle Genetics, Inc., Bothell, WA, United States of America.
authors: Andrew B
authors: AB
authors: Waight
authors: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.
authors: Katja
authors: K
authors: Bargsten
authors: Department of Protein Sciences, Seattle Genetics, Inc., Bothell, WA, United States of America.
authors: Svetlana
authors: S
authors: Doronina
authors: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.
authors: Michel O
authors: MO
authors: Steinmetz
authors: Department of Protein Sciences, Seattle Genetics, Inc., Bothell, WA, United States of America.
authors: Django
authors: D
authors: Sussman
authors: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.
authors: Andrea E
authors: AE
authors: Prota
mesh_terms: D062365:Aminobenzoates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D020836:Protein Structure, Quaternary; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D062365:Aminobenzoates; D009842:Oligopeptides; D014404:Tubulin; D050257:Tubulin Modulators; C543533:auristatin; D014747:Vinblastine