@article {Prota2021.07.20.453061, author = {Andrea E. Prota and Daniel Lucena-Agell and Yuntao Ma and Juan Est{\'e}vez-Gallego and Carlos Roca and Fernando Josa-Prado and Kenneth Goossens and Juan Francisco Gim{\'e}nez-Abi{\'a}n and Shuo Li and {\'A}ngeles Canales and Katja Bargsten and Jos{\'e} Manuel Andreu and Karl-Heinz Altmann and Natacha Olieric and Shinji Kamimura and Tobias M{\"u}hlethaler and Mar{\'\i}a A. Oliva and Michel O. Steinmetz and Wei-Shuo Fang and J. Fernando D{\'\i}az}, title = {Crystal structures of taxane-tubulin complexes: Implications for the mechanism of microtubule stabilization by Taxol}, elocation-id = {2021.07.20.453061}, year = {2021}, doi = {10.1101/2021.07.20.453061}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Paclitaxel (Taxol{\textregistered}) 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.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2021/07/21/2021.07.20.453061}, eprint = {https://www.biorxiv.org/content/early/2021/07/21/2021.07.20.453061.full.pdf}, journal = {bioRxiv} }