Abstract.
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters, WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of crucial importance for catalysis.
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Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001
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Prosperi-Meys, C., Wouters, J., Galleni, M. et al. Substrate binding and catalytic mechanism of class B β-lactamases: a molecular modelling study. CMLS, Cell. Mol. Life Sci. 58, 2136–2143 (2001). https://doi.org/10.1007/PL00000843
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DOI: https://doi.org/10.1007/PL00000843