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Cited by 234Microtubule and mitosis dynamicsCancer Treatment and PharmacologySynthesis and biological activity

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

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Kellogg, Elizabeth H., Hejab, Nisreen M.A., Howes, Stuart, Northcote, Peter, Miller, John H., Díaz, J. Fernando, Downing, Kenneth H., Nogales, Eva·2017·Journal of Molecular Biology
DOI 10.1016/j.jmb.2017.01.001PMC PMC5325780
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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.

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  • Paclitaxel expands the microtubule lattice in the longitudinal direction.

    “Paclitaxel is known to expand the microtubule lattice in the longitudinal direction 40,66 , an effect that could be readily observed by imaging microtubules sparsely labelled by fluorescent tubulin (Fig. 4g,i).”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [66]

    The Results section, “Effect of different MSAs on MT lattice parameters” (page unavailable), reports longitudinal lattice expansion when Taxol is added to unassembled tubulin. It also reports that adding Taxol to pre-formed microtubules produces an axial repeat very similar to the drug-free lattice, so the unqualified claim omits an important condition. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Diversity of microtubule conformations includes differences in protofilament number, longitudinal compaction or expansion, and dimer twist.

    “Diversity of microtubule conformations includes differences in protofilament number, longitudinal compaction or expansion, and dimer twist 63,66,71,72 (Extended Data Fig. 6c).”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [66]

  • The Taxol-induced expansion observed in vitro (41.2-42.0 Å) is considerably smaller than the average hyper-expansion of 42.6 Å measured in situ.

    “Remarkably, the Taxol-induced expansion to 41.2–42.0 Å observed in vitro (Alushin et al., 2014; Estevez-Gallego et al., 2020; Kellogg et al., 2017; Rai et al., 2020; Vale et al., 1994) is considerably smaller than the average hyper-expansion of 42.6 Å measured using our in situ approach.”

    From StableMARK-decorated microtubules in cells have expanded lattices (2025) · cites this paper as Kellogg et al., 2017

  • Taxol can alter the lattice spacing of microtubules in vitro.

    “drugs like the anti-cancer drug Taxol (paclitaxel) can alter the lattice spacing of the microtubule in vitro (Kellogg et al., 2017).”

    From StableMARK-decorated microtubules in cells have expanded lattices (2025) · cites this paper as Kellogg et al., 2017

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Research works printed but not linked: 51

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Authors
Kellogg, E. H., Hejab, N. M. A., Howes, S., Northcote, P., Miller, J. H., Díaz, J. F., Downing, K. H., & Nogales, E.
Affiliations
  • Lawrence Berkeley National Laboratory (US)
  • University of California, Berkeley (US)
  • Victoria University of Wellington (NZ)
  • Consejo Superior de Investigaciones Científicas (ES)
  • QB3 (US)
Corresponding author
Nogales, Eva
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2017-03
Volume
429
Issue
5
Pages
633-646
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2017.01.001
PMC
PMC5325780
OpenAlex
W2575108092
Cited by
234
References
53
Citations by year
2026: 24 · 2025: 27 · 2024: 19 · 2023: 26 · 2022: 27 · 2021: 18 · 2020: 29 · 2019: 29 · 2018: 24 · 2017: 11
FWCI
13.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • Office of Science of the U.S. Department of Energy (DE-AC02-05CH11231)
  • NIH (GM51487, S2010/BMD-2457 BIPEDD2)
  • Ministerio de Economia y Competitividad (BIO2013-42984-R)
  • Comunidad Autónoma de Madrid
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords
microtubule stabilizers, taxanes, paclitaxel, zampanolide, beta-tubulin, drug binding sites, lateral interactions, anticancer agents, combination therapy
MeSH terms
Antineoplastic Agents, Binding Sites, Bridged-Ring Compounds, Image Processing, Computer-Assisted, Microtubules, Proteins, Tubulin, Paclitaxel, Macrolides, Cryoelectron Microscopy, Taxoids

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