Structural insights into the design of inhibitors for the L1 metallo-beta-lactamase from Stenotrophomonas maltophilia.
One mechanism by which bacteria can escape the action of beta-lactam antibiotics is the production of metallo-beta-lactamases. Inhibition of these enzymes should restore the action of these widely used antibiotics. The tetrameric enzyme L1 from Stenotrophomonas maltophilia was used as a model system to determine a series of high-resolution crystal structures of apo, mono and bi-metal substituted proteins as well as protein-inhibitor complexes. Unexpectedly, although the apo structure revealed only few significant structural differences from the holo structure, some inhibitors were shown to induce amino acid side-chain rotations in the tightly packed active site. Moreover, one inhibitor employs a new binding mode in order to interact with the di-zinc center. This structural information could prove essential in the process of elucidation of the mode of interaction between a putative lead compound and metallo-beta-lactamases, one of the main steps in structure-based drug design.
Nauton
L
L
Institut de Biologie Structurale Jean-Pierre Ebel (UMR 5075;CNRS;CEA;UJF), 41, rue Jules Horowitz, F-38027 Grenoble Cedex 1, France.
Kahn
R
R
Garau
G
G
Hernandez
J F
JF
Dideberg
O
O
D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001051:Apoenzymes / Q000737:chemistry; D001665:Binding Sites; D002216:Captopril / Q000378:metabolism; D002511:Cephalosporins / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009070:Moxalactam / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D020615:Stenotrophomonas maltophilia / Q000201:enzymology*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013431:Sulfates / Q000737:chemistry; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction; D015032:Zinc / Q000378:metabolism; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001051:Apoenzymes; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008024:Ligands; D013431:Sulfates; D065093:beta-Lactamase Inhibitors; D014867:Water; D002216:Captopril; C088032:beta-lactamase L1; D001618:beta-Lactamases; C021720:nitrocefin; D015032:Zinc; D009070:Moxalactam