title: Structure-based design of a potent transition state analogue for TEM-1 beta-lactamase.
abstract: The structure of the plasmid-mediated beta-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 A 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 beta-lactamase reaction pathway. The design principles of this highly effective inhibitor (Ki = 110 nM) and the resulting structural and mechanistic implications are presented.
authors: Department of Biochemistry, University of Alberta, Edmonton, Canada.
authors: N C
authors: NC
authors: Strynadka
authors: R
authors: R
authors: Martin
authors: S E
authors: SE
authors: Jensen
authors: M
authors: M
authors: Gold
authors: J B
authors: JB
authors: Jones
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D001665:Binding Sites; D001897:Boronic Acids / Q000737:chemistry*; D003461:Crystallography; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D018716:Molecular Mimicry; D010400:Penicillin G / Q000737:chemistry; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: C100971:1-acetamido-2-(3-carboxyphenyl)ethane boronic acid; D000081:Acetamides; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1; D010400:Penicillin G