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X-ray Analysis of the NMC-A β-Lactamase at 1.64-Å Resolution, a Class A Carbapenemase with Broad Substrate Specificity

Abstract : The treatment of infectious diseases by penicillin and cephalosporin antibiotics is continuously challenged by the emergence and the dissemination of the numerous TEM and SHV mutant ␤-lactamases with extended sub-strate profiles. These class A ␤-lactamases nevertheless remain inefficient against carbapenems, the most effective antibiotics against clinically relevant pathogens. A new member of this enzyme class, NMC-A, was recently reported to hydrolyze at high rates, and hence destroy, all known ␤-lactam antibiotics, including carbapenems and cephamycins. The crystal structure of NMC-A was solved to 1.64-Å resolution, and reveals modifications in the topology of the substrate-binding site. While preserving the geometry of the essential catalytic residues, the active site of the enzyme presents a disulfide bridge between residues 69 and 238, and certain other structural differences compared with the other ␤-lactamases. These unusual features in class A ␤-lactamases involve amino acids that participate in enzyme-substrate interactions , which suggested that these structural factors should be related to the very broad substrate specificity of this enzyme. The comparison of the NMC-A structure with those of other class A enzymes and enzyme-ligand complexes, indicated that the position of Asn-132 in NMC-A provides critical additional space in the region of the protein where the poorer substrates for class A ␤-lactamases, such as cephamycins and carbapenems, need to be accommodated.
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Peter Swarén, Laurent Maveyraud, Xavier Raquet, Stéphanie Cabantous, Colette Duez, et al.. X-ray Analysis of the NMC-A β-Lactamase at 1.64-Å Resolution, a Class A Carbapenemase with Broad Substrate Specificity. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 1998, 273 (41), pp.26714-26721. ⟨10.1074/jbc.273.41.26714⟩. ⟨hal-03004553⟩



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