Structural and Functional Analysis of the Complex between Citrate and the Zinc Peptidase Carboxypeptidase A
Fernández, Daniel (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Boix i Borràs, Esther (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Pallarès i Goitiz, Irantzu (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Avilés, Francesc X. (Francesc Xavier) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Vendrell i Roca, Josep (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí"

Date: 2011
Abstract: A high-resolution carboxypeptidase-Zn 2+ -citrate complex was studied by X-ray diffraction and enzyme kinetics for the first time. The citrate molecule acts as a competitive inhibitor of this benchmark zinc-dependent peptidase, chelating the catalytic zinc ion in the active site of the enzyme and inducing a conformational change such that carboxypeptidase adopts the conformation expected to occur by substrate binding. Citrate adopts an extended conformation with half of the molecule facing the zinc ion, while the other half is docked in the S1′ hydrophobic specificity pocket of the enzyme, in contrast with the binding mode expected for a substrate like phenylalanine or a peptidomimetic inhibitor like benzylsuccinic acid. Combined structural and enzymatic analysis describes the characteristics of the binding of this ligand that, acting against physiologically relevant zinc-dependent proteases, may serve as a general model in the design of new drug-protecting molecules for the oral delivery of drugs of peptide origin.
Note: Número d'acord de subvenció MICINN/BIO2007/68046
Note: Número d'acord de subvenció AGAUR/2005/SGR-1037
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Published in: Enzyme research, Vol. 2011 (July 2011) , art. 128676, ISSN 2090-0414

PMID: 21804935


8 p, 935.8 KB

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Articles > Published articles

 Record created 2018-01-25, last modified 2019-07-17



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