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oai:repisalud.isciii.es:20.500.12105/75552024-09-27T10:16:27Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607

00925njm 22002777a 4500 dc Field, Jessica J author Pera, Benet author Calvo, Enrique author Canales, Angeles author Zurwerra, Didier author Trigili, Chiara author Rodríguez-Salarichs, Javier author Matesanz, Ruth author Kanakkanthara, Arun author Wakefield, St John author Singh, A Jonathan author Jiménez-Barbero, Jesús author Northcote, Peter author Miller, John H author Lopez, Juan Antonio author Hamel, Ernest author Barasoain, Isabel author Altmann, Karl-Heinz author Díaz, José Fernando author 2012-06-22 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. Chem Biol. 2012; 19(6):686-98 10.1016/j.chembiol.2012.05.008 1879-1301 10745521 Chemistry & biology 22726683 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