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 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.
García-Saez
Isabel
I
Laboratoire de Cristallographie Macromoléculaire, Institut de Biologie Structurale Jean-Pierre Ebel (CNRS-Commissariat à l'Energie Atomique, Saclay, France.
Hopkins
Julie
J
Papamicael
Cyril
C
Franceschini
Nicola
N
Amicosante
Gianfranco
G
Rossolini
Gian Maria
GM
Galleni
Moreno
M
Frère
Jean-Marie
JM
Dideberg
Otto
O
D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D002216:Captopril / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D005417:Flavobacterium / Q000737:chemistry*; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D015032:Zinc / Q000737:chemistry; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D002216:Captopril; D001618:beta-Lactamases; D015032:Zinc