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

Nature Structural Biology volume 3, pages 688–695 (1996)Cite this article

Abstract

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 (Ki=110 nM) and the resulting structural and mechanistic implications are presented.

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Authors and Affiliations

  1. Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    Natalie C.J. Strynadka

  2. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 1A1, Canada

    Richard Martin & J. Bryan Jones

  3. Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    S.E. Jensen

  4. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada

    Marvin Gold

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  1. Natalie C.J. Strynadka
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  4. Marvin Gold
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  5. J. Bryan Jones
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Strynadka, N., Martin, R., Jensen, S. et al. Structure-based design of a potent transition state analogue for TEM-1 β-lactamase. Nat Struct Mol Biol 3, 688–695 (1996). https://doi.org/10.1038/nsb0896-688

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