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J. Biol. Chem., Vol. 282, Issue 32, 23129-23139, August 10, 2007

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Activation of Inhibitors by Sortase Triggers Irreversible Modification of the Active Site^*

Anthony W. Maresso, Ruiying Wu, Justin W. Kern, Rongguang Zhang, Dorota Janik^¶, Dominique M. Missiakas, Mark-Eugene Duban^¶, Andrzej Joachimiak, and Olaf Schneewind¹

From the Department of Microbiology, University of Chicago, Chicago, Illinois 60637, the Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, and the ^¶Laboratory for the Design of Bioactive Molecules, Department of Chemistry and Physics, Chicago State University, Chicago, Illinois 60628

Sortases anchor surface proteins to the cell wall of Gram-positive pathogens through recognition of specific motif sequences. Loss of sortase leads to large reductions in virulence, which identifies sortase as a target for the development of antibacterials. By screening 135,625 small molecules for inhibition, we report here that aryl (-amino)ethyl ketones inhibit sortase enzymes from staphylococci and bacilli. Inhibition of sortases occurs through an irreversible, covalent modification of their active site cysteine. Sortases specifically activate this class of molecules via -elimination, generating a reactive olefin intermediate that covalently modifies the cysteine thiol. Analysis of the three-dimensional structure of Bacillus anthracis sortase B with and without inhibitor provides insights into the mechanism of inhibition and reveals binding pockets that can be exploited for drug discovery.

Received for publication, March 2, 2007 , and in revised form, May 24, 2007.

^* This work was supported by National Institutes of Health Grants AI38897 and AI057153 (to O. S.), GM074942 and GM62414 (to A. J.), and GM08043 and National Science Foundation Grant 9351490 (to M.-E. D. and Chicago State University) and by the U. S. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357 (to A. J.). The authors acknowledge membership within and support from the Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (GLRCE, NIAID-NIH Award 1-U54-AI-057153). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Tables S1–S3.

The atomic coordinates and structure factors (code 2OQW and 2OQZ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed: Dept. of Microbiology, University of Chicago, 920 E. 58th St., Chicago, IL 60637. Tel.: 773-834-9060; Fax: 773-834-8150; E-mail: oschnee{at}bsd.uchicago.edu.

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