Structural basis for the rational design of new anti-Brucella agents: the crystal structure of the C366S mutant of L-histidinol dehydrogenase from Brucella suis

Katia D'ambrosio; Marie Lopez; Nina A Dathan; Safia Ouahrani-Bettache; Stephan Köhler; Giuseppina Ascione; Simona Maria Monti; Jean-Yves Winum; Giuseppina De Simone

doi:10.1016/j.biochi.2013.09.028

Structural basis for the rational design of new anti-Brucella agents: the crystal structure of the C366S mutant of L-histidinol dehydrogenase from Brucella suis

Biochimie. 2014 Feb:97:114-20. doi: 10.1016/j.biochi.2013.09.028. Epub 2013 Oct 17.

Authors

Katia D'ambrosio¹, Marie Lopez², Nina A Dathan¹, Safia Ouahrani-Bettache³, Stephan Köhler³, Giuseppina Ascione¹, Simona Maria Monti⁴, Jean-Yves Winum⁵, Giuseppina De Simone⁶

Affiliations

¹ Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
² Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France; Centre d'Etudes d'Agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR 5236 CNRS-UM1-UM2, 1919 Route de Mende, 34293 Montpellier, France.
³ Centre d'Etudes d'Agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR 5236 CNRS-UM1-UM2, 1919 Route de Mende, 34293 Montpellier, France.
⁴ Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Napoli, Italy. Electronic address: marmonti@unina.it.
⁵ Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
⁶ Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Napoli, Italy. Electronic address: gdesimon@unina.it.

PMID: 24140957
DOI: 10.1016/j.biochi.2013.09.028

Abstract

L-Histidinol dehydrogenase from Brucella suis (BsHDH) is an enzyme involved in the histidine biosynthesis pathway which is absent in mammals, thus representing a very interesting target for the development of anti-Brucella agents. In this paper we report the crystallographic structure of a mutated form of BsHDH both in its unbound form and in complex with a nanomolar inhibitor. These studies provide the first structural background for the rational design of potent HDH inhibitors, thus offering new hints for clinical applications.

Keywords: Brucella suis; Drug design; Inhibitor; X-ray crystallography; l-Histidinol dehydrogenase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Oxidoreductases / antagonists & inhibitors
Alcohol Oxidoreductases / chemistry*
Alcohol Oxidoreductases / genetics
Amino Acid Sequence
Anti-Bacterial Agents / chemistry*
Bacterial Proteins / antagonists & inhibitors
Bacterial Proteins / chemistry*
Bacterial Proteins / genetics
Brucella suis / chemistry*
Brucella suis / enzymology
Butanones / chemistry*
Catalytic Domain
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors / chemistry*
Escherichia coli / enzymology
Escherichia coli / genetics
Gene Expression
Histidine / chemistry
Histidine / metabolism
Imidazoles / chemistry*
Molecular Docking Simulation
Molecular Sequence Data
Mutation
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Sequence Alignment
Sequence Homology, Amino Acid

Substances

3-amino-4-(1H-imidazol-5-yl)-1-(4-(phenylmethoxy)phenyl)butan-2-one
Anti-Bacterial Agents
Bacterial Proteins
Butanones
Enzyme Inhibitors
Imidazoles
Recombinant Proteins
Histidine
Alcohol Oxidoreductases
histidinol dehydrogenase