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

Elizabeth H Kellogg; Nisreen M.A Hejab; Stuart Howes; Peter Northcote; John H Miller; J. Fernando Díaz; Kenneth H Downing; Eva Nogales

doi:10.1016/j.jmb.2017.01.001

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

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

Elizabeth H Kellogg, Nisreen M.A Hejab, Stuart Howes, Peter Northcote, John H Miller, J. Fernando Díaz, Kenneth H Downing and Eva Nogales

Journal of molecular biology, Vol.429(5), pp.633-646

03/10/2017

DOI: https://doi.org/10.1016/j.jmb.2017.01.001

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https://hdl.handle.net/2376/104377

PMCID: PMC5325780

PMID: 28104363

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Abstract

microtubule

peloruside

microtubule-stabilizing agents

Taxol

cryo-EM

zampanolide

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. [Display omitted] •High-resolution cryo-EM reconstructions of diverse MSAs•Taxane-binding results in MT structural heterogeneity.•Peloruside binding regularizes the MT lattice.•Peloruside has an overriding effect when combined with Taxol.

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Title: Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures
Creators: Elizabeth H Kellogg - Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Nisreen M.A Hejab - Graduate Group in Comparative Biochemistry, UC Berkeley, CA 94720, USA
Stuart Howes - Biophysics Graduate Group, University of California, Berkeley, CA 94720, USA
Peter Northcote - Centre for Biodiscovery, Victoria University of Wellington, 6140, Wellington, New Zealand
John H Miller - Centre for Biodiscovery, Victoria University of Wellington, 6140, Wellington, New Zealand
J. Fernando Díaz - Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
Kenneth H Downing - Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Eva Nogales - Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Publication Details: Journal of molecular biology, Vol.429(5), pp.633-646
Academic Unit: School of Engineering and Applied Sciences (TRIC)
Publisher: Elsevier Ltd
Identifiers: 99900546891401842
Language: English
Resource Type: Journal article