Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures
Abstract
A number of microtubule (MT)-stabilizing agents (MSAs) have demonstrated or predicted potential as anticancer agents, but a detailed structural basis for their mechanism of action is still lacking. We have obtained high-resolution (3.9–4.2 Å) cryo-electron microscopy (cryo-EM) reconstructions of MTs stabilized by the taxane-site binders Taxol and zampanolide, and by peloruside, which targets a distinct, non-taxoid pocket on β-tubulin. We find that each molecule has unique distinct structural effects on the MT lattice structure. Peloruside acts primarily at lateral contacts and has an effect on the “seam” of heterologous interactions, enforcing a conformation more similar to that of homologous (i.e., non-seam) contacts by which it regularizes the MT lattice. In contrast, binding of either Taxol or zampanolide induces MT heterogeneity. In doubly bound MTs, peloruside overrides the heterogeneity induced by Taxol binding. Our structural analysis illustrates distinct mechanisms of these drugs for stabilizing the MT lattice and is of relevance to the possible use of combinations of MSAs to regulate MT activity and improve therapeutic potential.
- Authors:
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1400021
- Alternate Identifier(s):
- OSTI ID: 1379773
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- Journal of Molecular Biology
- Additional Journal Information:
- Journal Name: Journal of Molecular Biology Journal Volume: 429 Journal Issue: 5; Journal ID: ISSN 0022-2836
- Publisher:
- Elsevier
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; cryo-EM; microtubule; microtubule-stabilizing agents; Taxol; peloruside; zampanolide
Citation Formats
Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Díaz, J. Fernando, Downing, Kenneth H., and Nogales, Eva. Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures. United Kingdom: N. p., 2017.
Web. doi:10.1016/j.jmb.2017.01.001.
Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Díaz, J. Fernando, Downing, Kenneth H., & Nogales, Eva. Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures. United Kingdom. https://doi.org/10.1016/j.jmb.2017.01.001
Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Díaz, J. Fernando, Downing, Kenneth H., and Nogales, Eva. Wed .
"Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures". United Kingdom. https://doi.org/10.1016/j.jmb.2017.01.001.
@article{osti_1400021,
title = {Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures},
author = {Kellogg, Elizabeth H. and Hejab, Nisreen M. A. and Howes, Stuart and Northcote, Peter and Miller, John H. and Díaz, J. Fernando and Downing, Kenneth H. and Nogales, Eva},
abstractNote = {A number of microtubule (MT)-stabilizing agents (MSAs) have demonstrated or predicted potential as anticancer agents, but a detailed structural basis for their mechanism of action is still lacking. We have obtained high-resolution (3.9–4.2 Å) cryo-electron microscopy (cryo-EM) reconstructions of MTs stabilized by the taxane-site binders Taxol and zampanolide, and by peloruside, which targets a distinct, non-taxoid pocket on β-tubulin. We find that each molecule has unique distinct structural effects on the MT lattice structure. Peloruside acts primarily at lateral contacts and has an effect on the “seam” of heterologous interactions, enforcing a conformation more similar to that of homologous (i.e., non-seam) contacts by which it regularizes the MT lattice. In contrast, binding of either Taxol or zampanolide induces MT heterogeneity. In doubly bound MTs, peloruside overrides the heterogeneity induced by Taxol binding. Our structural analysis illustrates distinct mechanisms of these drugs for stabilizing the MT lattice and is of relevance to the possible use of combinations of MSAs to regulate MT activity and improve therapeutic potential.},
doi = {10.1016/j.jmb.2017.01.001},
journal = {Journal of Molecular Biology},
number = 5,
volume = 429,
place = {United Kingdom},
year = {Wed Mar 01 00:00:00 EST 2017},
month = {Wed Mar 01 00:00:00 EST 2017}
}
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https://doi.org/10.1016/j.jmb.2017.01.001
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