Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7555
Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
Field, Jessica J | Pera, Benet | Calvo, Enrique CNIC | Canales, Angeles | Zurwerra, Didier | Trigili, Chiara | Rodríguez-Salarichs, Javier | Matesanz, Ruth | Kanakkanthara, Arun | Wakefield, St John | Singh, A Jonathan | Jiménez-Barbero, Jesús | Northcote, Peter | Miller, John H | Lopez, Juan Antonio CNIC | Hamel, Ernest | Barasoain, Isabel | Altmann, Karl-Heinz | Díaz, José Fernando
Chem Biol. 2012; 19(6):686-98
Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to β-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in α,β-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates β-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.
Antineoplastic Agents | Binding Sites | Bridged-Ring Compounds | Cell Proliferation | Dimerization | Dose-Response Relationship, Drug | Drug Screening Assays, Antitumor | Humans | Kinetics | Macrolides | Magnetic Resonance Spectroscopy | Microtubules | Models, Molecular | Molecular Structure | Structure-Activity Relationship | Taxoids | Tubulin | Tumor Cells, Cultured
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