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Título: | Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands |
Autor: | Balaguer, Francisco de Asís CSIC ORCID; Mühlethaler, Tobias; Estévez-Gallego, Juan CSIC ORCID ; Calvo, Enrique; Giménez-Abián, Juan F. CSIC ; Risinger, April L.; Sorensen, Erik J.; Vanderwal, Christopher D.; Altmann, Karl-Heinz; Mooberry, Susan; Steinmetz, Michel O.; Oliva, María A. CSIC ORCID ; Prota, Andrea E.; Díaz, José Fernando CSIC ORCID | Palabras clave: | Cyclostreptin Tubulin Microtubules Multidrug resistance Taxanes |
Fecha de publicación: | 20-mar-2019 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | International Journal of Molecular Sciences 20(6): 1392 (2019) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.3390/ijms20061392 | URI: | http://hdl.handle.net/10261/178957 | DOI: | 10.3390/ijms20061392 | ISSN: | 1661-6596 | E-ISSN: | 1422-0067 |
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