A unique mode of microtubule stabilization induced by peloruside A |
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Authors: | Huzil J Torin Chik John K Slysz Gordon W Freedman Holly Tuszynski Jack Taylor Richard E Sackett Dan L Schriemer David C |
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Institution: | 1 Division of Experimental Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2 2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 3 Department of Chemistry and Biochemistry and the Walther Cancer Research Center, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA 4 Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, 9 Memorial Drive, Bethesda, MD 20892-0924, USA |
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Abstract: | 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 α/β-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 β-tubulin at a previously unknown ligand site, rather than on α-tubulin as suggested in earlier studies. |
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Keywords: | MSA microtubule-stabilizing agent GTP guanosine 5&prime -triphosphate HDX-MS hydrogen-deuterium exchange mass spectrometry LC-MS liquid chromatography-mass spectrometry GMPCPP guanosine-5&prime -[(α β)-methylene]triphosphate MD molecular dynamics |
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