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Open AccessArticle

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

1
Structural and Chemical Biology Department. Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
2
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland
3
Unidad de Proteómica. Centro Nacional de Investigaciones Cardiovasculares, CNIC. Melchor Fernández de Almagro 3, 28029 Madrid, Spain
4
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
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Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
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Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA
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ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zürich, Switzerland
8
University of Basel, Biozentrum, 4056 Basel, Switzerland
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1392; https://doi.org/10.3390/ijms20061392
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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