Dynamics induced by β-lactam antibiotics in the active site of Bacillus subtilis L,D-transpeptidase

Structure
Lauriane LecoqJean-Pierre Simorre

Abstract

β-lactams inhibit peptidoglycan polymerization by acting as suicide substrates of essential d,d-transpeptidases. Bypass of these enzymes by unrelated l,d-transpeptidases results in β-lactam resistance, although carbapenems remain unexpectedly active. To gain insight into carbapenem specificity of l,d-transpeptidases (Ldts), we solved the nuclear magnetic resonance (NMR) structures of apo and imipenem-acylated Bacillus subtilis Ldt and show that the cysteine nucleophile is present as a neutral imidazole-sulfhydryl pair in the substrate-free enzyme. NMR relaxation dispersion does not reveal any preexisting conformational exchange in the apoenzyme, and change in flexibility is not observed upon noncovalent binding of β-lactams (K(D) > 37.5 mM). In contrast, covalent modification of active cysteine by both carbapenems and 2-nitro-5-thiobenzoate induces backbone flexibility that does not result from disruption of the imidazole-sulfhydryl proton interaction or steric hindrance. The chemical step of the reaction determines enzyme specificity since no differences in drug affinity were observed.

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Citations

Mar 12, 2015·Acta Crystallographica. Section D, Biological Crystallography·Jaslyn E M M WongMickaël Blaise
Sep 4, 2013·Acta Crystallographica. Section D, Biological Crystallography·Stefania CorrealeRita Berisio
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Nov 28, 2014·Journal of the American Chemical Society·Paul SchandaJean-Pierre Simorre
May 15, 2012·Structure·Soumya De, Lawrence P McIntosh

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