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

J Biol Chem. 2003 Jun 27;278(26):23868-73. doi: 10.1074/jbc.M301062200. Epub 2003 Apr 8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Binding Sites
  • Captopril / chemistry*
  • Captopril / metabolism
  • Crystallization
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Flavobacterium / chemistry*
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Zinc / chemistry
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism

Substances

  • Bacterial Proteins
  • Enzyme Inhibitors
  • Captopril
  • beta-Lactamases
  • Zinc