Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics

Waight, Andrew B.; Bargsten, Katja; Doronina, Svetlana; Steinmetz, Michel O.; Sussman, Django; Prota, Andrea E.; Komarova, ed., Yulia

doi:10.1371/journal.pone.0160890

Title: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics

Journal Article · Fri Aug 12 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0160890· OSTI ID:1337464

Waight, Andrew B.; Bargsten, Katja; Doronina, Svetlana; Steinmetz, Michel O.; Sussman, Django; Prota, Andrea E.; Komarova, ed., Yulia

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.

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Research Organization:: Seattle Genetics, Inc., Bothell, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Swiss National Science Foundation (SNSF); Seattle Genetics Inc

Grant/Contract Number:: AC02-05CH11231; 310030B_138659

OSTI ID:: 1337464

Alternate ID(s):: OSTI ID: 1903867

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Vol. 11 Journal Issue: 8; ISSN 1932-6203

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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hydrogen bonding
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Title: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics

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