The 1.5-A structure of Chryseobacterium meningosepticum zinc beta-lactamase in complex with the inhibitor, D-captopril

The crystal structure of the class-B beta-lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, d-captopril, has been solved at 1.5-A resolution. The enzyme has the typical alphabeta/betaalpha metallo-beta-lactamase fold and the characterist...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-06, Vol.278 (26), p.23868-23873
Main Authors: García-Saez, Isabel, Hopkins, Julie, Papamicael, Cyril, Franceschini, Nicola, Amicosante, Gianfranco, Rossolini, Gian Maria, Galleni, Moreno, Frère, Jean-Marie, Dideberg, Otto
Format: Article
Language:English
Subjects:
Bacterial Proteins - chemistry
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Binding Sites
Captopril - chemistry
Captopril - metabolism
Chemical Sciences
Crystallization
Crystallography, X-Ray
Enzyme Inhibitors - chemistry
Flavobacterium - chemistry
Molecular Structure
Organic chemistry
Protein Binding
Protein Conformation
Zinc - chemistry
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Summary:The crystal structure of the class-B beta-lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, d-captopril, has been solved at 1.5-A resolution. The enzyme has the typical alphabeta/betaalpha metallo-beta-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M301062200