The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor

The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the ac...

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Autores: Fernández, Daniel, Testero, Sebastian Andres, Vendrell, Josep, Avilés, Francesc X., Mobashery, Shahriar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/133270
Acceso en línea:http://hdl.handle.net/11336/133270
Access Level:acceso abierto
Palabra clave:M14 FAMILY OF PROTEASES
MECHANISM-BASED INACTIVATION
METALLOPEPTIDASE
THIIRANE
X-RAY CRYSTALLOGRAPHY
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
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oai_identifier_str oai:ri.conicet.gov.ar:11336/133270
network_acronym_str AR
network_name_str Argentina
repository_id_str
spelling The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitorFernández, DanielTestero, Sebastian AndresVendrell, JosepAvilés, Francesc X.Mobashery, ShahriarM14 FAMILY OF PROTEASESMECHANISM-BASED INACTIVATIONMETALLOPEPTIDASETHIIRANEX-RAY CRYSTALLOGRAPHYhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1' specificity pocket of the enzyme. The inhibitor molecule is distorted at the position of the carbon atom that is involved in the ester bond linkage on one side and the zinc coordination on the other. This particular type of thiirane-based metalloprotease inhibitor is for the first time analyzed in complex to the target protease at high resolution and may be used as a general model for zinc-dependent proteases.Fil: Fernández, Daniel. Universitat Autònoma de Barcelona; EspañaFil: Testero, Sebastian Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. University of Notre Dame; Estados UnidosFil: Vendrell, Josep. Universitat Autònoma de Barcelona; EspañaFil: Avilés, Francesc X.. Universitat Autònoma de Barcelona; EspañaFil: Mobashery, Shahriar. University of Notre Dame; Estados UnidosWiley Blackwell Publishing, Inc2010-01info: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/11336/133270Fernández, Daniel; Testero, Sebastian Andres; Vendrell, Josep; Avilés, Francesc X.; Mobashery, Shahriar; The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor; Wiley Blackwell Publishing, Inc; Chemical Biology & Drug Design; 75; 1; 1-2010; 29-341747-0277CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908478/info:eu-repo/semantics/altIdentifier/doi/10.1111/j.1747-0285.2009.00907.xinfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/full/10.1111/j.1747-0285.2009.00907.xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:58:24Zoai:ri.conicet.gov.ar:11336/133270instacron: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:34982024-05-08 13:58:24.392CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
title The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
spellingShingle The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
Fernández, Daniel
M14 FAMILY OF PROTEASES
MECHANISM-BASED INACTIVATION
METALLOPEPTIDASE
THIIRANE
X-RAY CRYSTALLOGRAPHY
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
title_short The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
title_full The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
title_fullStr The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
title_full_unstemmed The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
title_sort The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor
dc.creator.none.fl_str_mv Fernández, Daniel
Testero, Sebastian Andres
Vendrell, Josep
Avilés, Francesc X.
Mobashery, Shahriar
author Fernández, Daniel
author_facet Fernández, Daniel
Testero, Sebastian Andres
Vendrell, Josep
Avilés, Francesc X.
Mobashery, Shahriar
author_role author
author2 Testero, Sebastian Andres
Vendrell, Josep
Avilés, Francesc X.
Mobashery, Shahriar
author2_role author
author
author
author
dc.subject.none.fl_str_mv M14 FAMILY OF PROTEASES
MECHANISM-BASED INACTIVATION
METALLOPEPTIDASE
THIIRANE
X-RAY CRYSTALLOGRAPHY
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
topic M14 FAMILY OF PROTEASES
MECHANISM-BASED INACTIVATION
METALLOPEPTIDASE
THIIRANE
X-RAY CRYSTALLOGRAPHY
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
description The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic zinc ion in a monodentate manner, inducing a change in the zinc ion geometry and coordination, while its benzyl group fits into the S1' specificity pocket of the enzyme. The inhibitor molecule is distorted at the position of the carbon atom that is involved in the ester bond linkage on one side and the zinc coordination on the other. This particular type of thiirane-based metalloprotease inhibitor is for the first time analyzed in complex to the target protease at high resolution and may be used as a general model for zinc-dependent proteases.
publishDate 2010
dc.date.none.fl_str_mv 2010-01
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/11336/133270
Fernández, Daniel; Testero, Sebastian Andres; Vendrell, Josep; Avilés, Francesc X.; Mobashery, Shahriar; The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor; Wiley Blackwell Publishing, Inc; Chemical Biology & Drug Design; 75; 1; 1-2010; 29-34
1747-0277
CONICET Digital
CONICET
url http://hdl.handle.net/11336/133270
identifier_str_mv Fernández, Daniel; Testero, Sebastian Andres; Vendrell, Josep; Avilés, Francesc X.; Mobashery, Shahriar; The X-ray structure of carboxypeptidase a inhibited by a thiirane mechanism-based ihibitor; Wiley Blackwell Publishing, Inc; Chemical Biology & Drug Design; 75; 1; 1-2010; 29-34
1747-0277
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908478/
info:eu-repo/semantics/altIdentifier/doi/10.1111/j.1747-0285.2009.00907.x
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/full/10.1111/j.1747-0285.2009.00907.x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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 15,811543

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