How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function
6 pags, 4 figs, 1 tab
| Autores: | , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/250481 |
| Acceso en línea: | http://hdl.handle.net/10261/250481 |
| Access Level: | acceso abierto |
| Palabra clave: | Allosteric mechanism Antibiotic resistance X-ray crystallography |
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oai:digital.csic.es:10261/250481 |
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How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological functionOtero, Lisandro H.Rojas-Altuve, A.Llarrull, Leticia I.Carrasco-López, C.Kumarasiri, M.Lastochkin, E.Fishovitz, J.Dawley, M.Hesek, D.Lee, M.Johnson, Jarrod W.Fisher, J.F.Chang, M.Mobashery, S.Hermoso, Juan A.Allosteric mechanismAntibiotic resistanceX-ray crystallography6 pags, 4 figs, 1 tabThe 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.Work in the United States was supported by National Institutes of Health Grants AI090818 and AI104987, and work in Spain was supported by Grants BFU2011-25326 (from the Spanish Ministry of Economy and Competitiveness) and S2010/BMD-2457 (from the Autonomous Government of Madrid).National Academy of Sciences (U.S.)National Institutes of Health (US)Ministerio de Economía y Competitividad (España)Comunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120132021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/250481reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2011-25326S2010/BMD-2457/BIPEDD2http://dx.doi.org/10.1073/pnas.1300118110Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2504812026-05-22T06:33:51Z |
| 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 H. 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 H. Rojas-Altuve, A. Llarrull, Leticia I. Carrasco-López, C. Kumarasiri, M. Lastochkin, E. Fishovitz, J. Dawley, M. Hesek, D. Lee, M. Johnson, Jarrod W. Fisher, J.F. Chang, M. Mobashery, S. Hermoso, Juan A. |
| author |
Otero, Lisandro H. |
| author_facet |
Otero, Lisandro H. Rojas-Altuve, A. Llarrull, Leticia I. Carrasco-López, C. Kumarasiri, M. Lastochkin, E. Fishovitz, J. Dawley, M. Hesek, D. Lee, M. Johnson, Jarrod W. Fisher, J.F. Chang, M. Mobashery, S. Hermoso, Juan A. |
| author_role |
author |
| author2 |
Rojas-Altuve, A. Llarrull, Leticia I. Carrasco-López, C. Kumarasiri, M. Lastochkin, E. Fishovitz, J. Dawley, M. Hesek, D. Lee, M. Johnson, Jarrod W. Fisher, J.F. Chang, M. Mobashery, S. Hermoso, Juan A. |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
National Institutes of Health (US) Ministerio de Economía y Competitividad (España) Comunidad de Madrid Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Allosteric mechanism Antibiotic resistance X-ray crystallography |
| topic |
Allosteric mechanism Antibiotic resistance X-ray crystallography |
| description |
6 pags, 4 figs, 1 tab |
| publishDate |
2013 |
| dc.date.none.fl_str_mv |
2013 2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/250481 |
| url |
http://hdl.handle.net/10261/250481 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
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#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2011-25326 S2010/BMD-2457/BIPEDD2 http://dx.doi.org/10.1073/pnas.1300118110 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
| dc.publisher.none.fl_str_mv |
National Academy of Sciences (U.S.) |
| publisher.none.fl_str_mv |
National Academy of Sciences (U.S.) |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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| repository.mail.fl_str_mv |
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1869406850038890496 |
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15,812429 |