HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 17, 17888-17896, April 23, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/17/17888    most recent M313123200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by García-Castellanos, R. Articles by Gomis-Rüth, F. X. Search for Related Content PubMed PubMed Citation Articles by García-Castellanos, R. Articles by Gomis-Rüth, F. X. Social Bookmarking                      What's this?

On the Transcriptional Regulation of Methicillin Resistance

MecI REPRESSOR IN COMPLEX WITH ITS OPERATOR^*

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

From the Institut de Biologia Molecular de Barcelona, CID-CSIC C/Jordi Girona, 18-26, 08034 Barcelona, Spain, the ^||Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, 30-387, Krakow, Poland, and the ^**Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602

Bacterial resistance to antibiotics poses a serious worldwide public health problem due to the high morbidity and mortality caused by infectious diseases. Most hospital-onset infections are associated with methicillin-resistant Staphylococcus aureus (MRSA) strains that have acquired multiple drug resistance to -lactam antibiotics. In a response to antimicrobial stress, nearly all clinical MRSA isolates produce -lactamase (BlaZ) and a penicillin-binding protein with low affinity for -lactam antibiotics (PBP2a, also known as PBP2' or MecA). Both effectors are regulated by homologous signal transduction systems consisting of a sensor/transducer and a transcriptional repressor. MecI (methicillin repressor) blocks mecA but also blaZ transcription and that of itself and the co-transcribed sensor/transducer. The structure of MecI in complex with a cognate operator double-stranded DNA reveals a homodimeric arrangement with a novel C-terminal spiral staircase dimerization domain responsible for dimer integrity. Each protomer interacts with the DNA major groove through a winged helix DNA-binding domain and specifically recognizes the nucleotide sequence 5'-Gua-Thy-Ade-X-Thy-3'. This results in an unusual convex bending of the DNA helix. The structure of this first molecular determinant of methicillin resistance in complex with its target DNA provides insights into its regulatory mechanism and paves the way for new antimicrobial strategies against MRSA.

Received for publication, December 2, 2003 , and in revised form, February 10, 2004.

The atomic coordinates and structure factors (code 1sax) 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 BIO2000-1659, BIO2003-00132 (to F. X. G.-R.), and BIO2002-00379 (to M. C.) from the Spanish Ministry for Science and Technology, Grant SGR2001-00346 from the Generalitat de Catalunya (to M. C. and F. X. G.-R.), and by Commission of the European Communities Centre of Excellence Program Grant ICA1-CT-2000-70012 (to J. P.). 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 Formación de Personal Investigador Ph.D. fellowship from the Spanish Ministry for Science and Technology.

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

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Boudet, V. Duval, H. Van Melckebeke, M. Blackledge, A. Amoroso, B. Joris, and J.-P. Simorre Conformational and thermodynamic changes of the repressor/DNA operator complex upon monomerization shed new light on regulation mechanisms of bacterial resistance against {beta}-lactam antibiotics Nucleic Acids Res., July 26, 2007; 35(13): 4384 - 4395. [Abstract] [Full Text] [PDF]

				L. Pecqueur, B. D'Autreaux, J. Dupuy, Y. Nicolet, L. Jacquamet, B. Brutscher, I. Michaud-Soret, and B. Bersch Structural Changes of Escherichia coli Ferric Uptake Regulator during Metal-dependent Dimerization and Activation Explored by NMR and X-ray Crystallography J. Biol. Chem., July 28, 2006; 281(30): 21286 - 21295. [Abstract] [Full Text] [PDF]

				S. Caputo, J. Couprie, I. Duband-Goulet, E. Konde, F. Lin, S. Braud, M. Gondry, B. Gilquin, H. J. Worman, and S. Zinn-Justin The Carboxyl-terminal Nucleoplasmic Region of MAN1 Exhibits a DNA Binding Winged Helix Domain J. Biol. Chem., June 30, 2006; 281(26): 18208 - 18215. [Abstract] [Full Text] [PDF]

				C. Fuda, D. Hesek, M. Lee, W. Heilmayer, R. Novak, S. B. Vakulenko, and S. Mobashery Mechanistic Basis for the Action of New Cephalosporin Antibiotics Effective against Methicillin- and Vancomycin-resistant Staphylococcus aureus J. Biol. Chem., April 14, 2006; 281(15): 10035 - 10041. [Abstract] [Full Text] [PDF]

				M. Doucleff, L. T. Malak, J. G. Pelton, and D. E. Wemmer The C-terminal RpoN Domain of {sigma}54 Forms an Unpredicted Helix-Turn-Helix Motif Similar to Domains of {sigma}70 J. Biol. Chem., December 16, 2005; 280(50): 41530 - 41536. [Abstract] [Full Text] [PDF]

				M. K. Safo, Q. Zhao, T.-P. Ko, F. N. Musayev, H. Robinson, N. Scarsdale, A. H.-J. Wang, and G. L. Archer Crystal Structures of the BlaI Repressor from Staphylococcus aureus and Its Complex with DNA: Insights into Transcriptional Regulation of the bla and mec Operons J. Bacteriol., March 1, 2005; 187(5): 1833 - 1844. [Abstract] [Full Text] [PDF]

				M. S. Wilke, T. L. Hills, H.-Z. Zhang, H. F. Chambers, and N. C. J. Strynadka Crystal Structures of the Apo and Penicillin-acylated Forms of the BlaR1 {beta}-Lactam Sensor of Staphylococcus aureus J. Biol. Chem., November 5, 2004; 279(45): 47278 - 47287. [Abstract] [Full Text] [PDF]