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Título: | Crystal structures of taxane-tubulin complexes: Implications for the mechanism of microtubule stabilization by Taxol |
Autor: | Prota, Andrea E.; Lucena-Agell, Daniel CSIC ORCID ; Ma, Yuntao; Estévez-Gallego, Juan CSIC ORCID ; Roca, Carlos CSIC ORCID; Josa-Prado, Fernando CSIC ORCID; Goossens, Kenneth; Giménez-Abián, Juan F. CSIC ; Li, Shuo; Canales, Ángeles CSIC ORCID; Bargsten, Katja; Andreu, José Manuel CSIC ORCID ; Altmann, Karl-Heinz; Olieric, Natacha; Kamimura, Shinji; Mühlethaler, Tobias; Oliva, María A. CSIC ORCID ; Steinmetz, Michel O.; Fang, Wei-Shuo; Díaz, José Fernando CSIC ORCID | Fecha de publicación: | 2021 | Citación: | BioRxiv (2021) | Resumen: | Paclitaxel (Taxol®) is a first-line chemotherapeutic drug that promotes the curved-to-straight conformational transition of tubulin, an activation step that is necessary for microtubule formation. Crystallization of Taxol bound to tubulin has been long elusive. We found that baccatin III, the core structure of paclitaxel which lacks the C13 side chain, readily co-crystallizes with curved tubulin. Tailor-made taxanes with alternative side chains also co-crystallized, allowing us to investigate their binding modes. Interestingly, these Taxol derived compounds lost their microtubule stabilizing activity and cytotoxicity but kept their full microtubule binding affinity, and all induced lattice expansion upon binding. Additional nuclear magnetic resonance studies propose that Taxol binds to a small fraction of straight tubulin present in solution. Our results suggest a mode of action of Taxol, where the core structure is responsible for the interacting energy while the bulky hydrophobic C13 side chain enables binding selectively to straight tubulin and promotes stabilization. | Descripción: | 30 p.-9 fig.-1 tab. | Versión del editor: | https://doi.org/10.1101/2021.07.20.453061 | URI: | http://hdl.handle.net/10261/278126 | DOI: | 10.1101/2021.07.20.453061 |
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PREPRINTCrystal_structures_of_taxane-tubulin_complexes_Imp.pdf | Preprint | 37,36 MB | Adobe PDF | Visualizar/Abrir |
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