Structure-based design of a potent transition state analogue for TEM-1 β-lactamase

The structure of the plasmid-mediated β-lactamase TEM-1 has been solved in complex with a designed boronic acid inhibitor (1R)-1-acetamido-2-(3-carboxyphenyl)ethane boronic acid at 1.7 Å resolution. The boronate inhibitor was designed based on the crystallographic coordinates of the acyl-enzyme intermediate of TEM-1 bound to the substrate penicillin G. The boronate–TEM-1 complex is highly ordered and defines a novel transition state analogue of the deacylation step in the β-lactamase reaction pathway. The design principles of this highly effective inhibitor ( K i =110 nM) and the resulting structural and mechanistic implications are presented.