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J Mol Biol. 2017 Mar 10;429(5):633-646. doi: 10.1016/j.jmb.2017.01.001. Epub 2017 Jan 17.

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

Author information

1
Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
2
Graduate Group in Comparative Biochemistry, UC Berkeley, CA 94720, USA.
3
Biophysics Graduate Group, University of California, Berkeley, CA 94720, USA.
4
Centre for Biodiscovery, Victoria University of Wellington, 6140, Wellington, New Zealand.
5
Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
6
Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; QB3 Institute and Molecular and Cell Biology Department, University of California, Berkeley, CA 94720-3220, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720-3220, USA. Electronic address: enogales@lbl.gov.

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 (3.9-4.2Å) 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.

KEYWORDS:

Taxol; cryo-EM; microtubule; microtubule-stabilizing agents; peloruside; zampanolide

PMID:
28104363
PMCID:
PMC5325780
DOI:
10.1016/j.jmb.2017.01.001
[Indexed for MEDLINE]
Free PMC Article

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