A POTENT NEW MODE OF BETA-LACTAMASE INHIBITION REVEALED BY THE 1.7 AX-RAY CRYSTALLOGRAPHIC STRUCTURE OF THE TEM-1-BLIP COMPLEX

The structure of TEM-1 beta-lactamase complexed with the inhibitor BLI P has been determined at 1.7 Angstrom resolution. The two tandemly rep eated domains of BLIP form a polar, concave surface that docks onto a predominantly polar, convex protrusion on the enzyme, The ability of B LIP to adapt to a Variety of class A beta-lactamases is most likely du e to an observed flexibility between the two domains of the inhibitor and to an extensive layer of water molecules entrapped between the enz yme and inhibitor, A beta-hairpin loop from domain 1 of BLIP is insert ed into the active site of the beta-lactamase. The carboxylate of Asp 49 forms hydrogen bonds to four conserved, catalytic residues in the b eta-lactamase, thereby mimicking the position of the penicillin G carb oxylate observed in the acyl-enzyme complex of TEM-1 with substrate, T his beta-hairpin may serve as a template with which to create a new fa mily of peptide-analogue beta-lactamase inhibitors.