STRUCTURE-BASED DESIGN OF A POTENT TRANSITION-STATE ANALOG FOR TEM-1 BETA-LACTAMASE

The structure of the plasmid-mediated beta-lactamase TEM-1 has been so lved in complex with a designed boronic acid inhibitor (1R)-1-acetamid o-2-(3-carboxyphenyl)ethane boronic acid at 1.7 Angstrom resolution. T he boronate inhibitor was designed based on the crystallographic coord inates of the acyl-enzyme intermediate of TEM-1 bound to the substrate penicillin G. The boronate-TEM-1 complex is highly ordered and define s a novel transition state analogue of the deacylation step in the bet a-lactamase reaction pathway, The design principles of this highly eff ective inhibitor (K-i=110 nM) and the resulting structural and mechani stic implications are presented.