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Title: Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures

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:
 [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [4] ;  [1] ;  [5]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Univ. of California, Berkeley, CA (United States)
  3. Victoria Univ. of Wellington, Wellington (New Zealand)
  4. Consejo Superior de Investigaciones Cientificas, Madrid (Spain)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Published Article
Journal Name:
Journal of Molecular Biology
Additional Journal Information:
Journal Volume: 429; Journal Issue: 5; Journal ID: ISSN 0022-2836
Publisher:
Elsevier
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cryo-EM; microtubule; microtubule-stabilizing agents; Taxol; peloruside; zampanolide
OSTI Identifier:
1400021
Alternate Identifier(s):
OSTI ID: 1379773

Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Diaz, 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 States: N. p., Web. doi:10.1016/j.jmb.2017.01.001.
Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Diaz, 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 States. doi:10.1016/j.jmb.2017.01.001.
Kellogg, Elizabeth H., Hejab, Nisreen M. A., Howes, Stuart, Northcote, Peter, Miller, John H., Diaz, J. Fernando, Downing, Kenneth H., and Nogales, Eva. 2017. "Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures". United States. doi: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 Diaz, 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 States},
year = {2017},
month = {1}
}