Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents

• DOI: 10.1126/science.1230582
• Publication Date: 2013-01-04T05:46:42Z
• Authors: Andrea E. Prota; Katja Bargsten; Didier Zurwerra; Jessica J. Field; José Fernando Díaz; Karl-Heinz Altmann; Michel O. Steinmetz
• Keywords: Taxane; Mechanism of Action; Kinesin

Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite importance MSAs medical applications and basic research, their molecular mechanisms action on tubulin microtubules remain elusive. We determined high-resolution crystal structures αβ-tubulin in complex with two unrelated MSAs, zampanolide epothilone A. Both compounds were bound to taxane pocket β-tubulin respective side chains induce structuring M-loop into a short helix. Because establishes lateral contacts microtubules, these findings explain how taxane-site promote microtubule assembly stability. Further, our results offer fundamental structural insights control dynamics.