Productive induced metastability in allosteric modulation of kinase function

Autores
Montes de Oca, Joan Manuel; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.
Fil: Montes de Oca, Joan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática; Argentina
Materia
Pharmaceuticals
Dehydron
Allostery
Kinase Inhibitor
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/12162
Acceder
id CONICETDig_d3fa1e28ba9904cc776910c5e8d869af
oai_identifier_str oai:ri.conicet.gov.ar:11336/12162
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Productive induced metastability in allosteric modulation of kinase functionMontes de Oca, Joan ManuelRodriguez Fris, Jorge ArielAppignanesi, Gustavo AdrianFernandez, ArielPharmaceuticalsDehydronAllosteryKinase Inhibitorhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.Fil: Montes de Oca, Joan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; ArgentinaFil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; ArgentinaFil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; ArgentinaFil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática; ArgentinaWiley2014-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdftext/plainhttp://hdl.handle.net/11336/12162Montes de Oca, Joan Manuel; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel; Productive induced metastability in allosteric modulation of kinase function; Wiley; Febs Journal; 281; 13; 7-2014; 3079-30911742-464Xenginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/febs.12844/abstractinfo:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1111/febs.12844info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:00Zoai:ri.conicet.gov.ar:11336/12162instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:00.416CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Productive induced metastability in allosteric modulation of kinase function
title Productive induced metastability in allosteric modulation of kinase function
spellingShingle Productive induced metastability in allosteric modulation of kinase function
Montes de Oca, Joan Manuel
Pharmaceuticals
Dehydron
Allostery
Kinase Inhibitor
title_short Productive induced metastability in allosteric modulation of kinase function
title_full Productive induced metastability in allosteric modulation of kinase function
title_fullStr Productive induced metastability in allosteric modulation of kinase function
title_full_unstemmed Productive induced metastability in allosteric modulation of kinase function
title_sort Productive induced metastability in allosteric modulation of kinase function
dc.creator.none.fl_str_mv Montes de Oca, Joan Manuel
Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author Montes de Oca, Joan Manuel
author_facet Montes de Oca, Joan Manuel
Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author_role author
author2 Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author2_role author
author
author
dc.subject.none.fl_str_mv Pharmaceuticals
Dehydron
Allostery
Kinase Inhibitor
topic Pharmaceuticals
Dehydron
Allostery
Kinase Inhibitor
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.
Fil: Montes de Oca, Joan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina
Fil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática; Argentina
description Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.
publishDate 2014
dc.date.none.fl_str_mv 2014-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/12162
Montes de Oca, Joan Manuel; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel; Productive induced metastability in allosteric modulation of kinase function; Wiley; Febs Journal; 281; 13; 7-2014; 3079-3091
1742-464X
url http://hdl.handle.net/11336/12162
identifier_str_mv Montes de Oca, Joan Manuel; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel; Productive induced metastability in allosteric modulation of kinase function; Wiley; Febs Journal; 281; 13; 7-2014; 3079-3091
1742-464X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/febs.12844/abstract
info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1111/febs.12844
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
text/plain
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269494664232960
score 13.13397

Publicaciones similares