Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis

Autores
Lisa, María Natalia; Gil, Magdalena; André Leroux, Gwénaëlle; Barilone, Nathalie; Durán, Rosario; Biondi, Ricardo Miguel; Alzari, Pedro M.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Summary Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.
Fil: Lisa, María Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Centre National de la Recherche Scientifique; Francia. Université Paris Diderot - Paris 7; Francia
Fil: Gil, Magdalena. Instituto Pasteur de Montevideo; Uruguay
Fil: André Leroux, Gwénaëlle. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Barilone, Nathalie. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Durán, Rosario. Instituto Pasteur de Montevideo; Uruguay
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alzari, Pedro M.. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
Materia
S/T PROTEIN KINASE
PknG
Mycobacterium tuberculosis
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:11336/185863
Acceder
id CONICETDig_948b50132f42ac93443c19e388d1334f
oai_identifier_str oai:ri.conicet.gov.ar:11336/185863
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosisLisa, María NataliaGil, MagdalenaAndré Leroux, GwénaëlleBarilone, NathalieDurán, RosarioBiondi, Ricardo MiguelAlzari, Pedro M.S/T PROTEIN KINASEPknGMycobacterium tuberculosishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Summary Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.Fil: Lisa, María Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Centre National de la Recherche Scientifique; Francia. Université Paris Diderot - Paris 7; FranciaFil: Gil, Magdalena. Instituto Pasteur de Montevideo; UruguayFil: André Leroux, Gwénaëlle. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Barilone, Nathalie. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Durán, Rosario. Instituto Pasteur de Montevideo; UruguayFil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alzari, Pedro M.. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaCell Press2015-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/185863Lisa, María Natalia; Gil, Magdalena; André Leroux, Gwénaëlle; Barilone, Nathalie; Durán, Rosario; et al.; Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis; Cell Press; Structure With Folding & Design.; 23; 6; 6-2015; 1039-10480969-2126CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0969212615001264info:eu-repo/semantics/altIdentifier/doi/10.1016/j.str.2015.04.001info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:57Zoai:ri.conicet.gov.ar:11336/185863instacron: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:34982025-09-29 09:49:57.437CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
title Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
spellingShingle Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
Lisa, María Natalia
S/T PROTEIN KINASE
PknG
Mycobacterium tuberculosis
title_short Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
title_full Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
title_fullStr Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
title_full_unstemmed Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
title_sort Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis
dc.creator.none.fl_str_mv Lisa, María Natalia
Gil, Magdalena
André Leroux, Gwénaëlle
Barilone, Nathalie
Durán, Rosario
Biondi, Ricardo Miguel
Alzari, Pedro M.
author Lisa, María Natalia
author_facet Lisa, María Natalia
Gil, Magdalena
André Leroux, Gwénaëlle
Barilone, Nathalie
Durán, Rosario
Biondi, Ricardo Miguel
Alzari, Pedro M.
author_role author
author2 Gil, Magdalena
André Leroux, Gwénaëlle
Barilone, Nathalie
Durán, Rosario
Biondi, Ricardo Miguel
Alzari, Pedro M.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv S/T PROTEIN KINASE
PknG
Mycobacterium tuberculosis
topic S/T PROTEIN KINASE
PknG
Mycobacterium tuberculosis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Summary Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.
Fil: Lisa, María Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Centre National de la Recherche Scientifique; Francia. Université Paris Diderot - Paris 7; Francia
Fil: Gil, Magdalena. Instituto Pasteur de Montevideo; Uruguay
Fil: André Leroux, Gwénaëlle. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Barilone, Nathalie. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Durán, Rosario. Instituto Pasteur de Montevideo; Uruguay
Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alzari, Pedro M.. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Francia
description Summary Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.
publishDate 2015
dc.date.none.fl_str_mv 2015-06
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/11336/185863
Lisa, María Natalia; Gil, Magdalena; André Leroux, Gwénaëlle; Barilone, Nathalie; Durán, Rosario; et al.; Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis; Cell Press; Structure With Folding & Design.; 23; 6; 6-2015; 1039-1048
0969-2126
CONICET Digital
CONICET
url http://hdl.handle.net/11336/185863
identifier_str_mv Lisa, María Natalia; Gil, Magdalena; André Leroux, Gwénaëlle; Barilone, Nathalie; Durán, Rosario; et al.; Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis; Cell Press; Structure With Folding & Design.; 23; 6; 6-2015; 1039-1048
0969-2126
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0969212615001264
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.str.2015.04.001
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
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
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_ 1844613542815203328
score 13.070432

Publicaciones similares