How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function

Autores
Otero, Lisandro Horacio; Rojas Altuve, Alzoray; Llarrull, Leticia Irene; Carrasco López, Cesar; Kumarasiri, Malika; Lastochkin, Elena; Fishovitz, Jennifer; Dawley, Matthew; Hesek, Dusan; Lee, Mijoon; Johnson, Jarrod W.; Fisher, Jed F.; Chang, Mayland; Mobashery, Shahriar; Hermoso, Juan A.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The highmolecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain - a remarkable 60 Å distant from the DD-transpeptidase active site - discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.
Fil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España. 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
Fil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
Fil: Llarrull, Leticia Irene. University of Notre Dame; Estados Unidos. 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
Fil: Carrasco López, Cesar. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
Fil: Kumarasiri, Malika. University of Notre Dame; Estados Unidos
Fil: Lastochkin, Elena. University of Notre Dame; Estados Unidos
Fil: Fishovitz, Jennifer. University of Notre Dame; Estados Unidos
Fil: Dawley, Matthew. University of Notre Dame; Estados Unidos
Fil: Hesek, Dusan. University of Notre Dame; Estados Unidos
Fil: Lee, Mijoon. University of Notre Dame; Estados Unidos
Fil: Johnson, Jarrod W.. University of Notre Dame; Estados Unidos
Fil: Fisher, Jed F.. University of Notre Dame; Estados Unidos
Fil: Chang, Mayland. University of Notre Dame; Estados Unidos
Fil: Mobashery, Shahriar. University of Notre Dame; Estados Unidos
Fil: Hermoso, Juan A.. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
Materia
ALLOSTERIC MECHANISM
ANTIBIOTIC RESISTANCE
X-RAY CRYSTALLOGRAPHY
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:11336/94276
Acceder
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network_name_str CONICET Digital (CONICET)
spelling How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological FunctionOtero, Lisandro HoracioRojas Altuve, AlzorayLlarrull, Leticia IreneCarrasco López, CesarKumarasiri, MalikaLastochkin, ElenaFishovitz, JenniferDawley, MatthewHesek, DusanLee, MijoonJohnson, Jarrod W.Fisher, Jed F.Chang, MaylandMobashery, ShahriarHermoso, Juan A.ALLOSTERIC MECHANISMANTIBIOTIC RESISTANCEX-RAY CRYSTALLOGRAPHYhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The highmolecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain - a remarkable 60 Å distant from the DD-transpeptidase active site - discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.Fil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España. 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; ArgentinaFil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; EspañaFil: Llarrull, Leticia Irene. University of Notre Dame; Estados Unidos. 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; ArgentinaFil: Carrasco López, Cesar. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; EspañaFil: Kumarasiri, Malika. University of Notre Dame; Estados UnidosFil: Lastochkin, Elena. University of Notre Dame; Estados UnidosFil: Fishovitz, Jennifer. University of Notre Dame; Estados UnidosFil: Dawley, Matthew. University of Notre Dame; Estados UnidosFil: Hesek, Dusan. University of Notre Dame; Estados UnidosFil: Lee, Mijoon. University of Notre Dame; Estados UnidosFil: Johnson, Jarrod W.. University of Notre Dame; Estados UnidosFil: Fisher, Jed F.. University of Notre Dame; Estados UnidosFil: Chang, Mayland. University of Notre Dame; Estados UnidosFil: Mobashery, Shahriar. University of Notre Dame; Estados UnidosFil: Hermoso, Juan A.. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; EspañaNational Academy of Sciences2013-10info: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/11336/94276Otero, Lisandro Horacio; Rojas Altuve, Alzoray; Llarrull, Leticia Irene; Carrasco López, Cesar; Kumarasiri, Malika; et al.; How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 110; 42; 10-2013; 16808-168130027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/cgi/pmidlookup?view=long&pmid=24085846info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1300118110info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800995/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:09:40Zoai:ri.conicet.gov.ar:11336/94276instacron: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:34982026-02-26 10:09:40.975CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
title How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
spellingShingle How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
Otero, Lisandro Horacio
ALLOSTERIC MECHANISM
ANTIBIOTIC RESISTANCE
X-RAY CRYSTALLOGRAPHY
title_short How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
title_full How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
title_fullStr How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
title_full_unstemmed How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
title_sort How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function
dc.creator.none.fl_str_mv Otero, Lisandro Horacio
Rojas Altuve, Alzoray
Llarrull, Leticia Irene
Carrasco López, Cesar
Kumarasiri, Malika
Lastochkin, Elena
Fishovitz, Jennifer
Dawley, Matthew
Hesek, Dusan
Lee, Mijoon
Johnson, Jarrod W.
Fisher, Jed F.
Chang, Mayland
Mobashery, Shahriar
Hermoso, Juan A.
author Otero, Lisandro Horacio
author_facet Otero, Lisandro Horacio
Rojas Altuve, Alzoray
Llarrull, Leticia Irene
Carrasco López, Cesar
Kumarasiri, Malika
Lastochkin, Elena
Fishovitz, Jennifer
Dawley, Matthew
Hesek, Dusan
Lee, Mijoon
Johnson, Jarrod W.
Fisher, Jed F.
Chang, Mayland
Mobashery, Shahriar
Hermoso, Juan A.
author_role author
author2 Rojas Altuve, Alzoray
Llarrull, Leticia Irene
Carrasco López, Cesar
Kumarasiri, Malika
Lastochkin, Elena
Fishovitz, Jennifer
Dawley, Matthew
Hesek, Dusan
Lee, Mijoon
Johnson, Jarrod W.
Fisher, Jed F.
Chang, Mayland
Mobashery, Shahriar
Hermoso, Juan A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALLOSTERIC MECHANISM
ANTIBIOTIC RESISTANCE
X-RAY CRYSTALLOGRAPHY
topic ALLOSTERIC MECHANISM
ANTIBIOTIC RESISTANCE
X-RAY CRYSTALLOGRAPHY
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The highmolecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain - a remarkable 60 Å distant from the DD-transpeptidase active site - discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.
Fil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España. 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
Fil: Rojas Altuve, Alzoray. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
Fil: Llarrull, Leticia Irene. University of Notre Dame; Estados Unidos. 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
Fil: Carrasco López, Cesar. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
Fil: Kumarasiri, Malika. University of Notre Dame; Estados Unidos
Fil: Lastochkin, Elena. University of Notre Dame; Estados Unidos
Fil: Fishovitz, Jennifer. University of Notre Dame; Estados Unidos
Fil: Dawley, Matthew. University of Notre Dame; Estados Unidos
Fil: Hesek, Dusan. University of Notre Dame; Estados Unidos
Fil: Lee, Mijoon. University of Notre Dame; Estados Unidos
Fil: Johnson, Jarrod W.. University of Notre Dame; Estados Unidos
Fil: Fisher, Jed F.. University of Notre Dame; Estados Unidos
Fil: Chang, Mayland. University of Notre Dame; Estados Unidos
Fil: Mobashery, Shahriar. University of Notre Dame; Estados Unidos
Fil: Hermoso, Juan A.. Consejo Superior de Investigaciones Científicas. Instituto de Química Física; España
description The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The highmolecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain - a remarkable 60 Å distant from the DD-transpeptidase active site - discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.
publishDate 2013
dc.date.none.fl_str_mv 2013-10
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/11336/94276
Otero, Lisandro Horacio; Rojas Altuve, Alzoray; Llarrull, Leticia Irene; Carrasco López, Cesar; Kumarasiri, Malika; et al.; How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 110; 42; 10-2013; 16808-16813
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/94276
identifier_str_mv Otero, Lisandro Horacio; Rojas Altuve, Alzoray; Llarrull, Leticia Irene; Carrasco López, Cesar; Kumarasiri, Malika; et al.; How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin-Resistance and Physiological Function; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 110; 42; 10-2013; 16808-16813
0027-8424
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.pnas.org/cgi/pmidlookup?view=long&pmid=24085846
info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1300118110
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800995/
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
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application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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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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