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:
- Publication Date:
- Research Org.:
- Seattle Genetics, Inc., Bothell, WA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); Swiss National Science Foundation (SNSF); Seattle Genetics Inc
- OSTI Identifier:
- 1337464
- Alternate Identifier(s):
- OSTI ID: 1903867
- Grant/Contract Number:
- AC02-05CH11231; 310030B_138659
- Resource Type:
- Published Article
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Name: PLoS ONE Journal Volume: 11 Journal Issue: 8; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; tubulins; crystal structure; hydrogen bonding; microtubes; nucleotides; dimers; valine; molecular structure
Citation Formats
Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., and Komarova, ed., Yulia. Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. United States: N. p., 2016.
Web. doi:10.1371/journal.pone.0160890.
Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., & Komarova, ed., Yulia. Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. United States. https://doi.org/10.1371/journal.pone.0160890
Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., and Komarova, ed., Yulia. Fri .
"Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics". United States. https://doi.org/10.1371/journal.pone.0160890.
@article{osti_1337464,
title = {Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics},
author = {Waight, Andrew B. and Bargsten, Katja and Doronina, Svetlana and Steinmetz, Michel O. and Sussman, Django and Prota, Andrea E. and Komarova, ed., Yulia},
abstractNote = {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.},
doi = {10.1371/journal.pone.0160890},
journal = {PLoS ONE},
number = 8,
volume = 11,
place = {United States},
year = {2016},
month = {8}
}
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