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dc.contributor.authorField, Jessica J
dc.contributor.authorPera, Benet
dc.contributor.authorCalvo, Enrique 
dc.contributor.authorCanales, Angeles
dc.contributor.authorZurwerra, Didier
dc.contributor.authorTrigili, Chiara
dc.contributor.authorRodríguez-Salarichs, Javier
dc.contributor.authorMatesanz, Ruth
dc.contributor.authorKanakkanthara, Arun
dc.contributor.authorWakefield, St John
dc.contributor.authorSingh, A Jonathan
dc.contributor.authorJiménez-Barbero, Jesús
dc.contributor.authorNorthcote, Peter
dc.contributor.authorMiller, John H
dc.contributor.authorLopez, Juan Antonio 
dc.contributor.authorHamel, Ernest
dc.contributor.authorBarasoain, Isabel
dc.contributor.authorAltmann, Karl-Heinz
dc.contributor.authorDíaz, José Fernando
dc.identifier.citationChem Biol. 2012; 19(6):686-98es_ES
dc.description.abstractZampanolide 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.es_ES
dc.description.sponsorshipJRS was supported by a fellowship from Programa de Cooperacion Cientıfica entre el Ministerio de Ciencia, Tecnologıas y Medio Ambiente de la Republica de Cuba (CITMA) y el CSIC. J.F. received a short-term fellowship from EMBO and a Professional Development Grant from the Genesis Oncology Trust. This work was supported in part by grants BIO2010-16351 and CTQ2009-08536 from Ministerio de Economia y Competitividad to J.F.D. and J.J.B., respectively, and grant S2010/BMD-2457 BIPEDD2 from Comunidad Autonoma de Madrid to J.F.D., the Cancer Society of New Zealand, and the Wellington Medical Research Foundation (J.M.). The CNIC is supported by the Ministerio de Economıa y Competitividad and the Fundacion Pro CNIC.es_ES
dc.subject.meshAntineoplastic Agents es_ES
dc.subject.meshBinding Sites es_ES
dc.subject.meshBridged-Ring Compounds es_ES
dc.subject.meshCell Proliferation es_ES
dc.subject.meshDimerization es_ES
dc.subject.meshDose-Response Relationship, Druges_ES
dc.subject.meshDrug Screening Assays, Antitumor es_ES
dc.subject.meshHumans es_ES
dc.subject.meshKinetics es_ES
dc.subject.meshMacrolides es_ES
dc.subject.meshMagnetic Resonance Spectroscopy es_ES
dc.subject.meshMicrotubules es_ES
dc.subject.meshModels, Moleculares_ES
dc.subject.meshMolecular Structure es_ES
dc.subject.meshStructure-Activity Relationship es_ES
dc.subject.meshTaxoids es_ES
dc.subject.meshTubulin es_ES
dc.subject.meshTumor Cells, Culturedes_ES
dc.titleZampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubuleses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderMinsterio de Ciencia, Tecnología y Medio Ambiente (Cuba)es_ES
dc.contributor.funderEuropean Molecular Biology Organization (EMBO)es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderComunidad de Madrides_ES
dc.contributor.funderCancer Society of New Zealandes_ES
dc.contributor.funderWellington Medical Research Foundationes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.identifier.journalChemistry & biologyes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómicaes_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional