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J. Biol. Chem., Vol. 278, Issue 26, 23868-23873, June 27, 2003

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The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc -Lactamase in Complex with the Inhibitor, D-Captopril^*

Isabel García-Sáez , Julie Hopkins , Cyril Papamicael , Nicola Franceschini ¶, Gianfranco Amicosante ¶, Gian Maria Rossolini ||, Moreno Galleni **, Jean-Marie Frère ** and Otto Dideberg  

From the Laboratoire de Cristallographie Macromoléculaire, Institut de Biologie Structurale Jean-Pierre Ebel (CNRS-Commissariat à l'Energie Atomique (Saclay, France)), 41, rue Jules Horowitz, F-38027 Grenoble Cedex 1, France, Oxford Center for Molecular Sciences, England, South Parks Rd., GB-OXFORD, OX1 3QY, United Kingdom, ^¶Dipartimento di Scienze e Tecnologie Biomediche, Università di L'Aquila, I-67100 L'Aquila, Italy, ^||Dipartimento di Biologia Moleculare, Sezione di Microbiologia, Università di Siena, I-53100 Siena, Italy, and ^**Laboratoire d'Enzymologie, Centre d'Ingénierie des Protéines, Institut de Chimie, Université de Liège, Sart Tilman, B-4000 Liège, Belgium

The crystal structure of the class-B -lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, D-captopril, has been solved at 1.5-Å resolution. The enzyme has the typical / metallo--lactamase fold and the characteristic two metal binding sites of members of the subclass B1, in which two Zn²⁺ ions were identified. D-Captopril, a diastereoisomer of the commercial drug, captopril, acts as an inhibitor by displacing the catalytic hydroxyl ion required for antibiotic hydrolysis and intercalating its sulfhydryl group between the two Zn²⁺ ions. Interestingly, D-captopril is located on one side of the active site cleft. The x-ray structure of the complex of the closely related enzyme, IMP-1, with a mercaptocarboxylate inhibitor, which also contains a sulfhydryl group bound to the two Zn²⁺ ions, shows the ligand to be located on the opposite side of the active site cleft. A molecule generated by fusion of these two inhibitors would cover the entire cleft, suggesting an interesting approach to the design of highly specific inhibitors.

Received for publication, January 31, 2003 , and in revised form, April 4, 2003.

The atomic coordinates and structure factors (code 1m2x) 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 by European Union Human and Mobility Grant HPRN-CT-2002-00264 and Belgian Government Grant PAI P5/33. 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.

To whom correspondence should be addressed. Tel.: 33-4-38-78-56-09; Fax: 33-4-38-78-54-94; E-mail: otto{at}ibs.fr.

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