Structure-based design of a potent transition state analogue for TEM-1 beta-lactamase |
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Authors: | NC Strynadka R Martin SE Jensen M Gold JB Jones |
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Affiliation: | Department of Biochemistry, University of Alberta, Edmonton, Canada. |
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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. |
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