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J. Biol. Chem., Vol. 278, Issue 41, 39897-39905, October 10, 2003

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Three-dimensional Structure of MecI

MOLECULAR BASIS FOR TRANSCRIPTIONAL REGULATION OF STAPHYLOCOCCAL METHICILLIN RESISTANCE^*

Raquel García-Castellanos  , Aniebrys Marrero  ¶, Goretti Mallorquí-Fernández  ||, Jan Potempa ** , Miquel Coll  and F. Xavier Gomis-Rüth  ||||

From the Institut de Biologia Molecular de Barcelona, Centre d'Investigació i Desenvolupament/Consell Superior d'Investigacions Científiques C/Jordi Girona, 18-26, 08034 Barcelona, Spain and the ^**Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland and the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602

Methicillin-resistant Staphylococcus aureus is the main cause of nosocomial and community-onset infections that affect millions of people worldwide. Some methicillin-resistant Staphylococcus aureus infections have become essentially untreatable by -lactams because of acquired molecular machineries enabling antibiotic resistance. Evasion from methicillin challenge is mainly achieved by the synthesis of a penicillin-binding protein of low affinity for antibiotics, MecA, that replaces regular penicillin-binding proteins in cell wall turnover when these have been inactivated by antibiotics. MecA synthesis is regulated by a signal transduction system consisting of the sensor/transducer MecR1 and the 14-kDa transcriptional repressor MecI (also known as methicillin repressor) that constitutively blocks mecA transcription. The three-dimensional structure of MecI reveals a dimer of two independent winged helix domains, each of which binds a palindromic DNA-operator half site, and two intimately intertwining dimerization domains of novel spiral staircase architecture, held together by a hydrophobic core. Limited proteolytic cleavage by cognate MecR1 within the dimerization domains results in loss of dimer interaction surface, dissociation, and repressor release, which triggers MecA synthesis. Structural information on components of the MecA regulatory pathway, in particular on methicillin repressor, the ultimate transcriptional trigger of mecA-encoded methicillin resistance, is expected to lead to the development of new antimicrobial drugs.

Received for publication, July 5, 2003 , and in revised form, July 21, 2003.

The atomic coordinates and structure factors (code 1okr) 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 Spanish Ministry for Science and Technology Grants BIO2000-1659 and BIO2003-00132 (to F. X. G. R.) and BIO2002-00379 (to M. C.) and Grant SGR2001-00346 from the Generalitat de Catalunya (to M. C.). 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 an FPI Ph.D. fellowship from the Spanish Ministry for Science and Technology.

^¶ Recipient of a postgraduate fellowship from "Fundación Carolina," Spanish Ministry of Foreign Affairs.

^|| Recipient of a fellowship from the University of Girona.

^|||| To whom correspondence should be addressed. Tel. 3493-400-61-44; Fax: 3493-204-59-04; E-mail: xgrcri{at}ibmb.csic.es.

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