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J. Biol. Chem., Vol. 280, Issue 35, 31249-31256, September 2, 2005

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Crystal Structure of the Actinomadura R39 DD-peptidase Reveals New Domains in Penicillin-binding Proteins^*

Eric Sauvage, Raphaël Herman, Stephanie Petrella, Colette Duez¶, Fabrice Bouillenne, Jean-Marie Frère, and Paulette Charlier

From the Centre d'Ingénierie des Protéines, Université de Liège, Institut de Physique B5, B-4000 Liège, Belgium

Actinomadura sp. R39 produces an exocellular DD-peptidase/penicillin-binding protein (PBP) whose primary structure is similar to that of Escherichia coli PBP4. It is characterized by a high -lactam-binding activity (second order rate constant for the acylation of the active site serine by benzylpenicillin: k/K = 300 mM^-1s^-1). The crystal structure of the DD-peptidase from Actinomadura R39 was solved at a resolution of 1.8 Å by single anomalous dispersion at the cobalt resonance wavelength. The structure is composed of three domains: a penicillin-binding domain similar to the penicillin-binding domain of E. coli PBP5 and two domains of unknown function. In most multimodular PBPs, additional domains are generally located at the C or N termini of the penicillin-binding domain. In R39, the other two domains are inserted in the penicillin-binding domain, between the SXXK and SXN motifs, in a manner similar to "Matryoshka dolls." One of these domains is composed of a five-stranded -sheet with two helices on one side, and the other domain is a double three-stranded -sheet inserted in the previous domain. Additionally, the 2.4-Å structure of the acyl-enzyme complex of R39 with nitrocefin reveals the absence of active site conformational change upon binding the -lactams.

Received for publication, March 24, 2005 , and in revised form, June 10, 2005.

This paper is dedicated to the memory of J.-M. Ghuysen who initiated the study of R39 more than thirty years ago.

The atomic coordinates and structure factors (code 1W79, 1W8Q, and 1W8Y) 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 the Belgian Program on Inter-university Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming (Grant PAI P5/33), by the Fonds National de la Recherche Scientifique (Grants IISN 4.4505.00, FRFC 9.45/9.99, FRFC 2.4.508.01.F, FRFC 9.4.538.03.F, and FRFC 2.4.524.03), and by the University of Liège (Fonds spéciaux, Crédit classique, 1999). 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.

A fellow of the French Fondation Recherche Médicale.

^¶ Chercheur Qualifié of the Fonds National de la Recherche Scientifique (Brussels, Belgium).

To whom correspondence should be addressed: Tel.: 32-43-66-36-20; Fax: 32-43-66-33-64; E-mail: eric.sauvage{at}ulg.ac.be.

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