ArticleCell cycle (Georgetown, Tex.)2011
Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding.
Article in Cell cycle (Georgetown, Tex.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Structural insight into the role of Gln293Met mutation on the Peloruside A/Laulimalide association with αβ-tubulin from molecular dynamics simulations, binding free energy calculations and weak interactions analysis.Journal of computer-aided molecular design · 2017Article
- Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration.International journal of molecular sciences · 2017Article
- Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.International journal of molecular sciences · 2017Article
- Conformation-activity relationships of polyketide natural products.Natural product reports · 2015Review
- Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities.Natural product reports · 2014Review
- Peloruside, laulimalide, and noscapine interactions with beta-tubulin.Pharmaceutical research · 2012Review
- Random mutagenesis of β-tubulin defines a set of dispersed mutations that confer paclitaxel resistance.Pharmaceutical research · 2012Article
- Low-dose laulimalide represents a novel molecular probe for investigating microtubule organization.Cell cycle (Georgetown, Tex.) · 2012Article
- Toward an enantioselective synthesis of (-)-zampanolide: preparation of the C9-C20 region.Organic letters · 2012Article
- Rapid access to conformational analogues of (+)-peloruside A.Organic letters · 2012Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Peloruside A is a microtubule-stabilizing macrolide that binds to beta tubulin at a site distinct from the taxol site. The site was previously identified by H-D exchange mapping and molecular docking as a region close to the outer surface of the microtubule and confined in a cavity surrounded by a continuous loop of protein folded so as to center on Y340. We have isolated a series of peloruside A-resistant lines of the human ovarian carcinoma cell line A2780(1A9) to better characterize this binding site and the consequences of altering residues in it. Four resistant lines (Pel A-D) are described with single-base mutations in class I β-tubulin that result in the following substitutions: R306H, Y340S, N337D, and A296S in various combinations. The mutations are localized to peptides previously identified by Hydrogen-Deuterium exchange mapping, and center on a cleft in which the drug side chain appears to dock. The Pel lines are 10-15-fold resistant to peloruside A and show cross resistance to laulimalide but not to any other microtubule stabilizers. They show no cross-sensitivity to any microtubule destabilizers, nor to two drugs with targets unrelated to microtubules. Peloruside A induces G2/M arrest in the Pel cell lines at concentrations 10-15 times that required in the parental line. The cells show notable changes in morphology compared to the parental line.
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