A potent new mode of beta-lactamase inhibition revealed by the 1.7 A X-ray crystallographic structure of the TEM-1-BLIP complex.
The structure of TEM-1 beta-lactamase complex with the inhibitor BLIP has been determined at 1.7 angstrom resolution. The two tandemly repeated domains of BLIP form a polar, concave surface that docks onto a predominantly polar, convex protrusion on the enzyme. The ability of BLIP to adapt to a variety of class A beta-lactamases is most likely due to an observed flexibility between the two domains of the inhibitor and to an extensive layer of water molecules entrapped between the enzyme and inhibitor. A beta-hairpin loop from domain 1 of BLIP is inserted into the active site of the beta-lactamase. The carboxylate of Asp 49 forms hydrogen bonds to four conserved, catalytic residues in the beta-lactamase, thereby mimicking the position of the penicillin G carboxylate observed in the acyl-enzyme complex of TEM-1 with substrate. This beta-hairpin may serve as a template with which to create a new family of peptide-analogue beta-lactamase inhibitors.
Strynadka
N C
NC
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Jensen
S E
SE
Alzari
P M
PM
James
M N
MN
D000595:Amino Acid Sequence; D001419:Bacteria / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003001:Cloning, Molecular; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
D001426:Bacterial Proteins; D011994:Recombinant Proteins; C065596:beta-lactamase-inhibitor protein, Streptomyces; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1