dc.contributor.author | Balaguer, Francisco de Asís | |
dc.contributor.author | Mühlethaler, Tobias | |
dc.contributor.author | Estévez-Gallego, Juan | |
dc.contributor.author | Calvo, Enrique | |
dc.contributor.author | Giménez-Abián, Juan Francisco | |
dc.contributor.author | Risinger, April L | |
dc.contributor.author | Sorensen, Erik J | |
dc.contributor.author | Vanderwal, Christopher D | |
dc.contributor.author | Altmann, Karl-Heinz | |
dc.contributor.author | Mooberry, Susan L | |
dc.contributor.author | Steinmetz, Michel O | |
dc.contributor.author | Oliva, María Ángela | |
dc.contributor.author | Prota, Andrea E | |
dc.contributor.author | Díaz, J Fernando | |
dc.date.accessioned | 2019-04-26T11:02:26Z | |
dc.date.available | 2019-04-26T11:02:26Z | |
dc.date.issued | 2019-03-20 | |
dc.identifier.citation | Int J Mol Sci. 2019; 20(6):E1392 | es_ES |
dc.identifier.issn | 1422-0067 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7516 | |
dc.description.abstract | It 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.sponsorship | This 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 discovery | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Multidisciplinary Digital Publishing Institute (MDPI) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Cyclostreptin | es_ES |
dc.subject | Microtubules | es_ES |
dc.subject | Multidrug resistance | es_ES |
dc.subject | Taxanes | es_ES |
dc.subject | Tubulin | es_ES |
dc.title | Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 30897704 | es_ES |
dc.format.volume | 20 | es_ES |
dc.format.number | 6 | es_ES |
dc.format.page | 1392 | es_ES |
dc.identifier.doi | 10.3390/ijms20061392 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | |
dc.contributor.funder | Swiss National Science Foundation | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1422-0067 | es_ES |
dc.identifier.journal | International journal of molecular sciences | es_ES |
dc.repisalud.orgCNIC | CNIC::Unidades técnicas::Proteómica / Metabolómica | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BFU2016-75319-R | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/RYC-2011-07900 | es_ES |
dc.rights.accessRights | open access | es_ES |