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Cellular and Molecular Life Sciences CMLS

, Volume 58, Issue 14, pp 2136–2143 | Cite as

Substrate binding and catalytic mechanism of class B β-lactamases: a molecular modelling study

  • C. Prosperi-Meys
  • J. Wouters
  • M. Galleni
  • J. Lamotte-Brasseur

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.

Key words. Metallo-β-lactamase; catalytic mechanism; molecular modelling; penicillin binding; molecular mechanics; zinc enzyme. 

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Copyright information

© Birkhäuser Verlag, 2001

Authors and Affiliations

  • C. Prosperi-Meys
    • 1
  • J. Wouters
    • 2
  • M. Galleni
    • 3
  • J. Lamotte-Brasseur
    • 3
  1. 1.Service de Physique Expérimentale, Institut de Physique (B5), Université de Liège, Sart-Tilman, 4000 Liège (Belgium)BE
  2. 2.FUNDP, 61, rue de Bruxelles, 5000 Namur (Belgium)BE
  3. 3.Centre d'Ingénierie des protéines, Institut de Chimie (B6), Université de Liège, Sart-Tilman, 4000 Liège (Belgium)BE

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