Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands

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, inclu...

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Autores: Balaguer, Francisco de Asís, Mühlethaler, Tobias, Estévez-Gallego, Juan, Calvo, Enrique, Giménez-Abián, Juan Francisco, Risinger, April L, Sorensen, Erik J, Vanderwal, Christopher D, Altmann, Karl-Heinz, Mooberry, Susan L, Steinmetz, Michel O, Oliva, María Ángela, Prota, Andrea E, Díaz, J Fernando
Formato: artículo
Fecha de publicación:2019
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7516
Acesso em linha:http://hdl.handle.net/20.500.12105/7516
Access Level:acceso abierto
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/7516
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spelling Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site LigandsBalaguer, Francisco de AsísMühlethaler, TobiasEstévez-Gallego, JuanCalvo, EnriqueGiménez-Abián, Juan FranciscoRisinger, April LSorensen, Erik JVanderwal, Christopher DAltmann, Karl-HeinzMooberry, Susan LSteinmetz, Michel OOliva, María ÁngelaProta, Andrea EDíaz, J FernandoIt 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.Multidisciplinary Digital Publishing Institute (MDPI)Ministerio de Economía y Competitividad (España)Ministerio de Ciencia e Innovación (España)Swiss National Science Foundation20192019-04-2620192019-03-2020192019-03-20journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/20.500.12105/7516reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES BFU2016-75319-R Not availableES RYC-2011-07900 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/75162026-06-12T12:43:37Z
dc.title.none.fl_str_mv Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
title Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
spellingShingle Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
Balaguer, Francisco de Asís
title_short Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
title_full Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
title_fullStr Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
title_full_unstemmed Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
title_sort Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
dc.creator.none.fl_str_mv Balaguer, Francisco de Asís
Mühlethaler, Tobias
Estévez-Gallego, Juan
Calvo, Enrique
Giménez-Abián, Juan Francisco
Risinger, April L
Sorensen, Erik J
Vanderwal, Christopher D
Altmann, Karl-Heinz
Mooberry, Susan L
Steinmetz, Michel O
Oliva, María Ángela
Prota, Andrea E
Díaz, J Fernando
author Balaguer, Francisco de Asís
author_facet Balaguer, Francisco de Asís
Mühlethaler, Tobias
Estévez-Gallego, Juan
Calvo, Enrique
Giménez-Abián, Juan Francisco
Risinger, April L
Sorensen, Erik J
Vanderwal, Christopher D
Altmann, Karl-Heinz
Mooberry, Susan L
Steinmetz, Michel O
Oliva, María Ángela
Prota, Andrea E
Díaz, J Fernando
author_role author
author2 Mühlethaler, Tobias
Estévez-Gallego, Juan
Calvo, Enrique
Giménez-Abián, Juan Francisco
Risinger, April L
Sorensen, Erik J
Vanderwal, Christopher D
Altmann, Karl-Heinz
Mooberry, Susan L
Steinmetz, Michel O
Oliva, María Ángela
Prota, Andrea E
Díaz, J Fernando
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia e Innovación (España)
Swiss National Science Foundation
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-04-26
2019
2019-03-20
2019
2019-03-20
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7516
url http://hdl.handle.net/20.500.12105/7516
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES BFU2016-75319-R Not available
ES RYC-2011-07900 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/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
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute (MDPI)
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute (MDPI)
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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