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J. Biol. Chem., Vol. 280, Issue 27, 25735-25742, July 8, 2005
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**
From the
Unité de Biochimie Structurale,
CNRS URA 2185, 25 rue du Docteur Roux and¶
Unité de Génétique
Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur
Roux, 75724 Paris, France and ||European
Synchrotron Radiation Facility, 6 rue Jules Horowitz, 38043 Grenoble Cedex,
France
The peroxiredoxin AhpC from Mycobacterium tuberculosis (MtAhpC) is
the foremost element of a NADH-dependent peroxidase and peroxynitrite
reductase system, where it directly reduces peroxides and peroxynitrite and is
in turn reduced by AhpD and other proteins. Overexpression of MtAhpC in
isoniazid-resistant strains of M. tuberculosis harboring mutations in
the catalase/peroxidase katG gene provides antioxidant protection and
may substitute for the lost enzyme activities. We report here the crystal
structure of oxidized MtAhpC trapped in an intermediate oligomeric state of
its catalytic cycle. The overall structure folds into a ring-shaped hexamer of
dimers instead of the usual pentamer of dimers observed in other reduced
peroxiredoxins. Although the general structure of the functional dimer is
similar to that of other 2-Cys peroxiredoxins, the
-helix containing
the peroxidatic cysteine Cys61 undergoes a unique rigid-body
movement to allow the formation of the disulfide bridge with the resolving
cysteine Cys174. This conformational rearrangement creates a large
internal cavity enclosing the active site, which might be exploited for the
design of inhibitors that could block the catalytic cycle. Structural and
mutagenesis evidence points to a model for the electron transfer pathway in
MtAhpC that accounts for the unusual involvement of three cysteine residues in
catalysis and suggests a mechanism by which MtAhpC can specifically interact
with different redox partners.
Received for publication, March 21, 2005 , and in revised form, May 2, 2005.
The atomic coordinates and structure factors (code 2BMX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported in part by grants from the Institut Pasteur (GPH-5), the Ministry of Research (Contract 01-B-0095), the European Union (X-TB, Contract QLK2-CT-2001-02018, and SPINE, Contract QLG2-CT-2002-00988), and the National Genopole Network, France (Contract RNG-2002-008). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Recipient of a fellowship from Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP) (Brazil). Present address:
Centro de Biologia Molecular Estrutural, Laboratório Nacional de Luz
Síncrotron, Caixa Postal 6192, CEP 13084-971, Campinas, Sao Paulo,
Brasil.
** To whom correspondence should be addressed: Unité de Biochimie Structurale, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: 33-145688607; Fax: 33-145688604; E-mail: alzari{at}pasteur.fr.
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