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Open AccessArticle

Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands

Structural and Chemical Biology Department. Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland
Unidad de Proteómica. Centro Nacional de Investigaciones Cardiovasculares, CNIC. Melchor Fernández de Almagro 3, 28029 Madrid, Spain
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA
ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zürich, Switzerland
University of Basel, Biozentrum, 4056 Basel, Switzerland
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1392;
Received: 28 February 2019 / Revised: 14 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands. View Full-Text
Keywords: cyclostreptin; tubulin; microtubules; multidrug resistance; taxanes cyclostreptin; tubulin; microtubules; multidrug resistance; taxanes
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Balaguer, F.A.; Mühlethaler, T.; Estévez-Gallego, J.; Calvo, E.; Giménez-Abián, J.F.; Risinger, A.L.; Sorensen, E.J.; Vanderwal, C.D.; Altmann, K.-H.; Mooberry, S.L.; Steinmetz, M.O.; Oliva, M.Á.; Prota, A.E.; Díaz, J.F. Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands. Int. J. Mol. Sci. 2019, 20, 1392.

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