title: Molecular mechanism of action of microtubule-stabilizing anticancer agents.
abstract: Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of β-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.
authors.affiliation: Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
authors.forename: Katja
authors.initials: K
authors.lastname: Bargsten
authors.forename: Didier
authors.initials: D
authors.lastname: Zurwerra
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Field
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002645:Chickens; D018360:Crystallography, X-Ray; D034261:Epothilones / Q000737:chemistry* / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects*; D017433:Protein Structure, Secondary; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D034261:Epothilones; D018942:Macrolides; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; C444900:zampanolide; C080625:taxane; C093787:epothilone A