title: Substrate binding and catalytic mechanism of class B beta-lactamases: a molecular modelling study.
abstract: Increased resistance to beta-lactam antibiotics is mainly due to beta-lactamases whose production by pathogenic bacteria makes their broad activity spectrum especially frightening. X-ray structures of several zinc beta-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 beta-lactamase to the beta-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 beta-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.
authors.affiliation: Service de Physique Expérimentale, Institut de Physique, Université de Liège, Sart-Tilman, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Prosperi-Meys
authors.forename: J
authors.initials: J
authors.lastname: Wouters
authors.forename: M
authors.initials: M
authors.lastname: Galleni
authors.forename: J
authors.initials: J
authors.lastname: Lamotte-Brasseur
mesh_terms: D001409:Bacillus cereus / Q000201:enzymology; D001665:Binding Sites / Q000502:physiology; D002384:Catalysis; D018360:Crystallography, X-Ray; D008024:Ligands; D046911:Macromolecular Substances; D008956:Models, Chemical; D008958:Models, Molecular; D010400:Penicillin G / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity / Q000502:physiology; D015032:Zinc / Q000737:chemistry; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification
chemical_list: D008024:Ligands; D046911:Macromolecular Substances; D001618:beta-Lactamases; D015032:Zinc; D010400:Penicillin G