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dc.contributor.authorField, Jessica J.es_ES
dc.contributor.authorPera, Benetes_ES
dc.contributor.authorEstévez-Gallego, Juanes_ES
dc.contributor.authorRodríguez-Salarichs, Javieres_ES
dc.contributor.authorSáez-Calvo, Gonzaloes_ES
dc.contributor.authorAndreu, José Manueles_ES
dc.contributor.authorDíaz, José Fernandoes_ES
dc.identifier.citationJ. Nat. Prod., Article ASAP (2017)es_ES
dc.description41 p.-8 fig.-2 tab. Field, Jessica J. et al.es_ES
dc.description.abstractThe marine natural product zampanolide and analogues thereof constitute a new chemotype of taxoid site microtubule-stabilizing agents with a covalent mechanism of action. Zampanolide-ligated tubulin has the switch-activation loop (M-loop) in the assembly prone form and, thus, represents an assembly activated state of the protein. In this study, we have characterized the biochemical properties of the covalently modified, activated tubulin dimer, and we have determined the effect of zampanolide on tubulin association and the binding of tubulin ligands at other binding sites. Tubulin activation by zampanolide does not affect its longitudinal oligomerization but does alter its lateral association properties. The covalent binding of zampanolide to β-tubulin affects both the colchicine site, causing a change of the quantum yield of the bound ligand, and the exchangeable nucleotide binding site, reducing the affinity for the nucleotide. While these global effects do not change the binding affinity of 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MTC) (a reversible binder of the colchicine site), the binding affinity of a fluorescent analogue of GTP (Mant-GTP) at the nucleotide E-site is reduced from 12 ± 2 × 105 M-1 in the case of unmodified tubulin to 1.4 ± 0.3 × 105 M-1 in the case of the zampanolide tubulin adduct, indicating signal transmission between the taxane site and the colchicine and nucleotide sites of β-tubulin.es_ES
dc.description.sponsorshipThis work was supported in part by grants BFU2016-75319-R (AEI/FEDER, UE) from Ministerio de Economia y Competitividad and the Cancer Society of New Zealand, and the Wellington Medical Research Foundation (JJF & JHM). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery”. The CNIC is supported by the Ministerio de Ciencia e Innovación and the Fundación Pro CNIC.es_ES
dc.publisherAmerican Chemical Societyes_ES
dc.titleZampanolide binding to tubulin indicates crosstalk of taxane site with colchicine and nucleotide siteses_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderCancer Society of New Zealandes_ES
dc.contributor.funderWellington Medical Research Foundationes_ES
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