A unique mode of microtubule stabilization induced by peloruside A

JOURNAL OF MOLECULAR BIOLOGY

卷:378

Article

Huzil, J. Torin²  Chik, John K.¹  Slysz, Gordon W.¹  Freedman, Holly²  Tuszynski, Jack²  Taylor, Richard E.^3,4  Sackett, Dan L.⁵  Schriemer, David C.¹ 

[1] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada

[2] Cross Canc Inst, Div Expt Oncol E, Edmonton, AB T6G 1Z2, Canada

[3] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

[4] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA

[5] NICHHD, NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA

关键词: microtubules;    peloruside A;    mass spectrometry;    hydrogen-deuterium exchange;    simulations;   

DOI  :  10.1016/j.jmb.2008.03.026

来源: Elsevier

【 摘 要 】

Microtubules are significant therapeutic targets for the treatment of cancer, where suppression of microtubule dynamicity by drugs such as paclitaxel forms the basis of clinical efficacy. Peloruside A, a macrolide isolated from New Zealand marine sponge Mycale hentscheli, is a microtubule-stabilizing agent that synergizes with taxoid drugs through a unique site and is an attractive lead compound in the development of combination therapies. We report here unique allosteric properties of microtubule stabilization via peloruside A and present a structural model of the peloruside-binding site. Using a strategy involving comparative hydrogen-deuterium exchange mass spectrometry of different microtubule-stabilizing agents, we suggest that taxoid-site ligands epothilone A and docetaxel stabilize microtubules primarily through improved longitudinal interactions centered on the interdimer interface, with no observable contributions from lateral interactions between protofilaments. The mode by which peloruside A achieves microtubule stabilization also involves the interdimer interface, but includes contributions from the alpha/beta-tubulin intradimer interface and protofilament contacts, both in the form of destabilizations. Using data-directed molecular docking simulations, we propose that peloruside A binds within a pocket on the exterior of beta-tubulin at a previously unknown ligand site, rather than on a-tubulin as suggested in earlier studies. (C) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

Free