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dc.contributor.author
Domingos, Renato M.
dc.contributor.author
Teixeira, Raphael D.
dc.contributor.author
Zeida Camacho, Ari Fernando
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Agudelo Suarez, William Armando
dc.contributor.author
Barros, Thiago
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Da Silva Neto, José F.
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Vieira, Plínio S.
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Murakami, Mario T.
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Farah, Chuck S.
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Estrin, Dario Ariel
dc.contributor.author
Netto, Luis E. S.
dc.date.available
2021-10-01T19:47:18Z
dc.date.issued
2020-05
dc.identifier.citation
Domingos, Renato M.; Teixeira, Raphael D.; Zeida Camacho, Ari Fernando; Agudelo Suarez, William Armando; Barros, Thiago; et al.; Substrate and product-assisted catalysis: Molecular aspects behind structural switches along organic hydroperoxide resistance protein catalytic cycle; American Chemical Society; ACS Catalysis; 10; 12; 5-2020; 6587-6602
dc.identifier.issn
2155-5435
dc.identifier.uri
http://hdl.handle.net/11336/142306
dc.description.abstract
Bacteria contain a large repertoire of enzymes to decompose oxidants, such as hydroperoxides. Among them, organic hydroperoxide resistance (Ohr) proteins play central roles in the bacterial response to fatty acid peroxides and peroxynitrite (Alegria et al. Ohr Plays a Central Role in Bacterial Responses against Fatty Acid Hydroperoxides and Peroxynitrite. Proc. Natl. Acad. Sci. USA 2017, 114, E132) and present distinct structural and biochemical features in comparison with mammalian Cys-based peroxidases. The molecular events associated with the high reactivity of Ohr enzymes toward hydroperoxides and its reducibility by lipoylated proteins (or dihydrolipoamide) are still elusive. Here, we report six crystallographic structures of two Ohr paralogs from Chromobacterium violaceum, including the complex with dihydrolipoamide. Comparison of these six structures with the other few Ohr structures available in public databases revealed conserved features in the active site, such as a hydrophobic collar. Together with classical, hybrid quantum-classical molecular dynamics simulations and point mutation analyses, we show that Ohr undergoes several structural switches to allow an energetically accessible movement of the loop containing the catalytic Arg, which is stabilized in the closed state when the catalytic Cys is reduced. The structure of Ohr in complex with its substrate (dihydrolipoamide) together with molecular simulations allowed us to characterize the reductive half of the catalytic pathway in detail. Notably, dihydrolipoamide favors Arg-loop closure, thereby assisting enzyme turnover. The conserved physicochemical properties of the Ohr active site and the mechanisms revealed here provide relevant information for the identification of inhibitors with therapeutic potential.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
DIHYDROLIPOAMIDE
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FATTY ACID HYDROPEROXIDES
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LIPOYLATED PROTEINS
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OHR/OSMC
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THIOL-DEPENDENT PEROXIDASES
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Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Substrate and product-assisted catalysis: Molecular aspects behind structural switches along organic hydroperoxide resistance protein catalytic cycle
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2021-09-07T18:39:40Z
dc.journal.volume
10
dc.journal.number
12
dc.journal.pagination
6587-6602
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Domingos, Renato M.. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Teixeira, Raphael D.. Universidade de Sao Paulo; Brasil
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Fil: Zeida Camacho, Ari Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina
dc.description.fil
Fil: Agudelo Suarez, William Armando. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina
dc.description.fil
Fil: Barros, Thiago. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Da Silva Neto, José F.. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Vieira, Plínio S.. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Murakami, Mario T.. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Farah, Chuck S.. Universidade de Sao Paulo; Brasil
dc.description.fil
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
dc.description.fil
Fil: Netto, Luis E. S.. Universidade de Sao Paulo; Brasil
dc.journal.title
ACS Catalysis
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1021/acscatal.0c01257
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acscatal.0c01257
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