Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules

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 N2...

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Autores: Field, Jessica J, Pera, Benet, Calvo, Enrique, Canales, Angeles, Zurwerra, Didier, Trigili, Chiara, Rodríguez-Salarichs, Javier, Matesanz, Ruth, Kanakkanthara, Arun, Wakefield, St John, Singh, A Jonathan, Jiménez-Barbero, Jesús, Northcote, Peter, Miller, John H, Lopez, Juan Antonio, Hamel, Ernest, Barasoain, Isabel, Altmann, Karl-Heinz, Díaz, José Fernando
Formato: artículo
Fecha de publicación:2012
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7555
Acesso em linha:http://hdl.handle.net/20.500.12105/7555
Access Level:acceso abierto
Palavra-chave:Antineoplastic Agents
Binding Sites
Bridged-Ring Compounds
Cell Proliferation
Dimerization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Macrolides
Magnetic Resonance Spectroscopy
Microtubules
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Taxoids
Tubulin
Tumor Cells, Cultured
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repository_id_str
spelling Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubulesField, Jessica JPera, BenetCalvo, EnriqueCanales, AngelesZurwerra, DidierTrigili, ChiaraRodríguez-Salarichs, JavierMatesanz, RuthKanakkanthara, ArunWakefield, St JohnSingh, A JonathanJiménez-Barbero, JesúsNorthcote, PeterMiller, John HLopez, Juan AntonioHamel, ErnestBarasoain, IsabelAltmann, Karl-HeinzDíaz, José FernandoAntineoplastic AgentsBinding SitesBridged-Ring CompoundsCell ProliferationDimerizationDose-Response Relationship, DrugDrug Screening Assays, AntitumorHumansKineticsMacrolidesMagnetic Resonance SpectroscopyMicrotubulesModels, MolecularMolecular StructureStructure-Activity RelationshipTaxoidsTubulinTumor Cells, CulturedZampanolide 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.ElsevierMinsterio de Ciencia, Tecnología y Medio Ambiente (Cuba)European Molecular Biology OrganizationMinisterio de Economía y Competitividad (España)Comunidad de Madrid (España)Cancer Society of New ZealandWellington Medical Research FoundationFundación ProCNIC20192019-05-0920122012-06-2220122012-06-22journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/7555reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES BIO2010-16351 Not availableES CTQ2009-08536 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/75552026-06-12T12:43:37Z
dc.title.none.fl_str_mv Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
title Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
spellingShingle Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
Field, Jessica J
Antineoplastic Agents
Binding Sites
Bridged-Ring Compounds
Cell Proliferation
Dimerization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Macrolides
Magnetic Resonance Spectroscopy
Microtubules
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Taxoids
Tubulin
Tumor Cells, Cultured
title_short Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
title_full Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
title_fullStr Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
title_full_unstemmed Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
title_sort Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules
dc.creator.none.fl_str_mv Field, Jessica J
Pera, Benet
Calvo, Enrique
Canales, Angeles
Zurwerra, Didier
Trigili, Chiara
Rodríguez-Salarichs, Javier
Matesanz, Ruth
Kanakkanthara, Arun
Wakefield, St John
Singh, A Jonathan
Jiménez-Barbero, Jesús
Northcote, Peter
Miller, John H
Lopez, Juan Antonio
Hamel, Ernest
Barasoain, Isabel
Altmann, Karl-Heinz
Díaz, José Fernando
author Field, Jessica J
author_facet Field, Jessica J
Pera, Benet
Calvo, Enrique
Canales, Angeles
Zurwerra, Didier
Trigili, Chiara
Rodríguez-Salarichs, Javier
Matesanz, Ruth
Kanakkanthara, Arun
Wakefield, St John
Singh, A Jonathan
Jiménez-Barbero, Jesús
Northcote, Peter
Miller, John H
Lopez, Juan Antonio
Hamel, Ernest
Barasoain, Isabel
Altmann, Karl-Heinz
Díaz, José Fernando
author_role author
author2 Pera, Benet
Calvo, Enrique
Canales, Angeles
Zurwerra, Didier
Trigili, Chiara
Rodríguez-Salarichs, Javier
Matesanz, Ruth
Kanakkanthara, Arun
Wakefield, St John
Singh, A Jonathan
Jiménez-Barbero, Jesús
Northcote, Peter
Miller, John H
Lopez, Juan Antonio
Hamel, Ernest
Barasoain, Isabel
Altmann, Karl-Heinz
Díaz, José Fernando
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Minsterio de Ciencia, Tecnología y Medio Ambiente (Cuba)
European Molecular Biology Organization
Ministerio de Economía y Competitividad (España)
Comunidad de Madrid (España)
Cancer Society of New Zealand
Wellington Medical Research Foundation
Fundación ProCNIC
dc.subject.none.fl_str_mv Antineoplastic Agents
Binding Sites
Bridged-Ring Compounds
Cell Proliferation
Dimerization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Macrolides
Magnetic Resonance Spectroscopy
Microtubules
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Taxoids
Tubulin
Tumor Cells, Cultured
topic Antineoplastic Agents
Binding Sites
Bridged-Ring Compounds
Cell Proliferation
Dimerization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Macrolides
Magnetic Resonance Spectroscopy
Microtubules
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Taxoids
Tubulin
Tumor Cells, Cultured
description 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.
publishDate 2012
dc.date.none.fl_str_mv 2012
2012-06-22
2012
2012-06-22
2019
2019-05-09
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7555
url http://hdl.handle.net/20.500.12105/7555
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES BIO2010-16351 Not available
ES CTQ2009-08536 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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