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dc.contributor.authorBalaguer, Francisco de Asís
dc.contributor.authorMühlethaler, Tobias
dc.contributor.authorEstévez-Gallego, Juan
dc.contributor.authorCalvo, Enrique 
dc.contributor.authorGiménez-Abián, Juan Francisco
dc.contributor.authorRisinger, April L
dc.contributor.authorSorensen, Erik J
dc.contributor.authorVanderwal, Christopher D
dc.contributor.authorAltmann, Karl-Heinz
dc.contributor.authorMooberry, Susan L
dc.contributor.authorSteinmetz, Michel O
dc.contributor.authorOliva, María Ángela
dc.contributor.authorProta, Andrea E
dc.contributor.authorDíaz, J Fernando
dc.date.accessioned2019-04-26T11:02:26Z
dc.date.available2019-04-26T11:02:26Z
dc.date.issued2019-03-20
dc.identifier.citationInt J Mol Sci. 2019; 20(6):E1392es_ES
dc.identifier.issn1422-0067es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7516
dc.description.abstractIt has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.es_ES
dc.description.sponsorshipThis research was funded by Ministerio de Economia y Competitividad grant BFU2016-75319-R to JFDP (both AEI/FEDER, UE); Ministerio de Ciencia e Innovación RYC-2011-07900 to MAO; Swiss National Science Foundation grant (31003A_166608) to MOS and CA121138 to SLM. The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature” from natural products chemistry to drug discoveryes_ES
dc.language.isoenges_ES
dc.publisherMDPIes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectcyclostreptines_ES
dc.subjectmicrotubuleses_ES
dc.subjectmultidrug resistancees_ES
dc.subjecttaxaneses_ES
dc.subjecttubulines_ES
dc.titleCrystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligandses_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID30897704es_ES
dc.format.volume20es_ES
dc.format.number6es_ES
dc.format.page1392es_ES
dc.identifier.doi10.3390/ijms20061392es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderMinisterio de Ciencia e Innovación (España)es_ES
dc.contributor.funderSwiss National Science Foundationes_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1422-0067es_ES
dc.identifier.journalInternational journal of molecular scienceses_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómicaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2016-75319-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RYC-2011-07900es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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