Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors

Autores
Ruggiero, Melina; Kerff, Frédéric; Herman, Raphaël; Sapunaric, Frédéric; Galleni, Moreno; Gutkind, Gabriel Osvaldo; Charlier, Paulette; Sauvage, Eric; Power, Pablo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
PER-2 belongs to a small (7 members to date) group of extended-spectrum β-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies towards most β-lactams. In this study, we determined the X-ray structure of PER-2 at 2.20 Å, and evaluated the possible role of several residues in the structure and activity towards β-lactams and mechanism-based inhibitors. PER-2 is defined by the presence of a singular trans bond between residues 166-167 that generates an inverted Ω loop, and an expanded fold of this domain that results in a wide active site cavity that allows for an efficient hydrolysis of antibiotics like the oxyimino-cephalosporins, and a series of exclusive interactions between residues not frequently involved in the stabilization of the active site in other class A β-lactamases. PER β-lactamases could be included within a cluster of evolutionary related enzymes harboring conserved residues Asp136 and Asn179. Other signature residues that define these enzymes seem to be Gln69, Arg220, Thr237, and probably Arg/Lys240A, with structurally important roles in the stabilization of the active site and proper orientation of catalytic water molecules, among others. We propose, supported by simulated models of PER-2 in combination with different β-lactams, the presence of a hydrogen-bond network connecting Ser70-Gln69-Water-Thr237-Arg220 that might be important for the proper activity and inhibition of the enzyme. Therefore, we could expect that mutations occurring in these positions will have impact in the overall hydrolytic behavior.
Fil: Ruggiero, Melina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Kerff, Frédéric. Université de Liège; Bélgica
Fil: Herman, Raphaël. Université de Liège; Bélgica
Fil: Sapunaric, Frédéric. Université de Liège; Bélgica
Fil: Galleni, Moreno. Université de Liège; Bélgica
Fil: Gutkind, Gabriel Osvaldo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Charlier, Paulette. Université de Liège; Bélgica
Fil: Sauvage, Eric. Université de Liège; Bélgica
Fil: Power, Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Materia
X-ray crystallography
ESBL
oxyimino-cephalosporins
PER-1
Arg220
clavulanic acid
Thr237
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:11336/30513
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/30513
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase InhibitorsRuggiero, MelinaKerff, FrédéricHerman, RaphaëlSapunaric, FrédéricGalleni, MorenoGutkind, Gabriel OsvaldoCharlier, PauletteSauvage, EricPower, PabloX-ray crystallographyESBLoxyimino-cephalosporinsPER-1Arg220clavulanic acidThr237https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1PER-2 belongs to a small (7 members to date) group of extended-spectrum β-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies towards most β-lactams. In this study, we determined the X-ray structure of PER-2 at 2.20 Å, and evaluated the possible role of several residues in the structure and activity towards β-lactams and mechanism-based inhibitors. PER-2 is defined by the presence of a singular trans bond between residues 166-167 that generates an inverted Ω loop, and an expanded fold of this domain that results in a wide active site cavity that allows for an efficient hydrolysis of antibiotics like the oxyimino-cephalosporins, and a series of exclusive interactions between residues not frequently involved in the stabilization of the active site in other class A β-lactamases. PER β-lactamases could be included within a cluster of evolutionary related enzymes harboring conserved residues Asp136 and Asn179. Other signature residues that define these enzymes seem to be Gln69, Arg220, Thr237, and probably Arg/Lys240A, with structurally important roles in the stabilization of the active site and proper orientation of catalytic water molecules, among others. We propose, supported by simulated models of PER-2 in combination with different β-lactams, the presence of a hydrogen-bond network connecting Ser70-Gln69-Water-Thr237-Arg220 that might be important for the proper activity and inhibition of the enzyme. Therefore, we could expect that mutations occurring in these positions will have impact in the overall hydrolytic behavior.Fil: Ruggiero, Melina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Kerff, Frédéric. Université de Liège; BélgicaFil: Herman, Raphaël. Université de Liège; BélgicaFil: Sapunaric, Frédéric. Université de Liège; BélgicaFil: Galleni, Moreno. Université de Liège; BélgicaFil: Gutkind, Gabriel Osvaldo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Charlier, Paulette. Université de Liège; BélgicaFil: Sauvage, Eric. Université de Liège; BélgicaFil: Power, Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaAmerican Society for Microbiology2014-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/30513Ruggiero, Melina; Kerff, Frédéric; Herman, Raphaël; Sapunaric, Frédéric; Galleni, Moreno; et al.; Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 58; 2; 7-2014; 5994-60020066-48041098-6596CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://aac.asm.org/content/58/10/5994.abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.00089-14info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:57:18Zoai:ri.conicet.gov.ar:11336/30513instacron: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 09:57:18.674CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
title Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
spellingShingle Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
Ruggiero, Melina
X-ray crystallography
ESBL
oxyimino-cephalosporins
PER-1
Arg220
clavulanic acid
Thr237
title_short Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
title_full Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
title_fullStr Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
title_full_unstemmed Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
title_sort Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors
dc.creator.none.fl_str_mv Ruggiero, Melina
Kerff, Frédéric
Herman, Raphaël
Sapunaric, Frédéric
Galleni, Moreno
Gutkind, Gabriel Osvaldo
Charlier, Paulette
Sauvage, Eric
Power, Pablo
author Ruggiero, Melina
author_facet Ruggiero, Melina
Kerff, Frédéric
Herman, Raphaël
Sapunaric, Frédéric
Galleni, Moreno
Gutkind, Gabriel Osvaldo
Charlier, Paulette
Sauvage, Eric
Power, Pablo
author_role author
author2 Kerff, Frédéric
Herman, Raphaël
Sapunaric, Frédéric
Galleni, Moreno
Gutkind, Gabriel Osvaldo
Charlier, Paulette
Sauvage, Eric
Power, Pablo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv X-ray crystallography
ESBL
oxyimino-cephalosporins
PER-1
Arg220
clavulanic acid
Thr237
topic X-ray crystallography
ESBL
oxyimino-cephalosporins
PER-1
Arg220
clavulanic acid
Thr237
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv PER-2 belongs to a small (7 members to date) group of extended-spectrum β-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies towards most β-lactams. In this study, we determined the X-ray structure of PER-2 at 2.20 Å, and evaluated the possible role of several residues in the structure and activity towards β-lactams and mechanism-based inhibitors. PER-2 is defined by the presence of a singular trans bond between residues 166-167 that generates an inverted Ω loop, and an expanded fold of this domain that results in a wide active site cavity that allows for an efficient hydrolysis of antibiotics like the oxyimino-cephalosporins, and a series of exclusive interactions between residues not frequently involved in the stabilization of the active site in other class A β-lactamases. PER β-lactamases could be included within a cluster of evolutionary related enzymes harboring conserved residues Asp136 and Asn179. Other signature residues that define these enzymes seem to be Gln69, Arg220, Thr237, and probably Arg/Lys240A, with structurally important roles in the stabilization of the active site and proper orientation of catalytic water molecules, among others. We propose, supported by simulated models of PER-2 in combination with different β-lactams, the presence of a hydrogen-bond network connecting Ser70-Gln69-Water-Thr237-Arg220 that might be important for the proper activity and inhibition of the enzyme. Therefore, we could expect that mutations occurring in these positions will have impact in the overall hydrolytic behavior.
Fil: Ruggiero, Melina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Kerff, Frédéric. Université de Liège; Bélgica
Fil: Herman, Raphaël. Université de Liège; Bélgica
Fil: Sapunaric, Frédéric. Université de Liège; Bélgica
Fil: Galleni, Moreno. Université de Liège; Bélgica
Fil: Gutkind, Gabriel Osvaldo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Charlier, Paulette. Université de Liège; Bélgica
Fil: Sauvage, Eric. Université de Liège; Bélgica
Fil: Power, Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
description PER-2 belongs to a small (7 members to date) group of extended-spectrum β-lactamases. It has 88% amino acid identity with PER-1 and both display high catalytic efficiencies towards most β-lactams. In this study, we determined the X-ray structure of PER-2 at 2.20 Å, and evaluated the possible role of several residues in the structure and activity towards β-lactams and mechanism-based inhibitors. PER-2 is defined by the presence of a singular trans bond between residues 166-167 that generates an inverted Ω loop, and an expanded fold of this domain that results in a wide active site cavity that allows for an efficient hydrolysis of antibiotics like the oxyimino-cephalosporins, and a series of exclusive interactions between residues not frequently involved in the stabilization of the active site in other class A β-lactamases. PER β-lactamases could be included within a cluster of evolutionary related enzymes harboring conserved residues Asp136 and Asn179. Other signature residues that define these enzymes seem to be Gln69, Arg220, Thr237, and probably Arg/Lys240A, with structurally important roles in the stabilization of the active site and proper orientation of catalytic water molecules, among others. We propose, supported by simulated models of PER-2 in combination with different β-lactams, the presence of a hydrogen-bond network connecting Ser70-Gln69-Water-Thr237-Arg220 that might be important for the proper activity and inhibition of the enzyme. Therefore, we could expect that mutations occurring in these positions will have impact in the overall hydrolytic behavior.
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/11336/30513
Ruggiero, Melina; Kerff, Frédéric; Herman, Raphaël; Sapunaric, Frédéric; Galleni, Moreno; et al.; Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 58; 2; 7-2014; 5994-6002
0066-4804
1098-6596
CONICET Digital
CONICET
url http://hdl.handle.net/11336/30513
identifier_str_mv Ruggiero, Melina; Kerff, Frédéric; Herman, Raphaël; Sapunaric, Frédéric; Galleni, Moreno; et al.; Crystal Structure of the Extended-Spectrum β-Lactamase PER-2 and Insights into the Role of Specific Residues in the Interaction with β-Lactams and β-Lactamase Inhibitors; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 58; 2; 7-2014; 5994-6002
0066-4804
1098-6596
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://aac.asm.org/content/58/10/5994.abstract
info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.00089-14
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
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
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
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score 13.13397

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