RT Journal Article
SR Electronic
T1 Crystal structures of taxane-tubulin complexes: Implications for the mechanism of microtubule stabilization by Taxol
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.20.453061
DO 10.1101/2021.07.20.453061
A1 Andrea E. Prota
A1 Daniel Lucena-Agell
A1 Yuntao Ma
A1 Juan Estévez-Gallego
A1 Carlos Roca
A1 Fernando Josa-Prado
A1 Kenneth Goossens
A1 Juan Francisco Giménez-Abián
A1 Shuo Li
A1 Ángeles Canales
A1 Katja Bargsten
A1 José Manuel Andreu
A1 Karl-Heinz Altmann
A1 Natacha Olieric
A1 Shinji Kamimura
A1 Tobias Mühlethaler
A1 María A. Oliva
A1 Michel O. Steinmetz
A1 Wei-Shuo Fang
A1 J. Fernando Díaz
YR 2021
UL http://biorxiv.org/content/early/2021/07/21/2021.07.20.453061.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.