Abstract
Metallo-beta-lactamases are bacterial enzymes that may function with either one or two zinc ions bound in the active site. In this work, the binding of benzylpenicillin to mono-zinc metallo-beta-lactamase from Bacillus cereus has been investigated in a docking procedure applying a combined quantum mechanical/molecular mechanical method as the final step. It is demonstrated that the substrate can bind with the carbonyl oxygen of the lactam ring coordinating to the zinc ion, and with the zinc-bound hydroxide ion in position for a nucleophilic attack on the carbonyl carbon of the lactam ring. In some structures, both the histidine and the cysteine at the other (unoccupied) metal-binding site are in a proper position to function as proton shuttles in proton transfer from the previously zinc-bound hydroxide, to the nitrogen in the lactam ring. In addition, the hydrophobic region formed by Phe34, Val39, Trp59, and Ala89 interacts with the phenyl group of benzylpenicillin, whereas the carboxylate group may be stabilized by Lys171 and Asn180. Alternatively, the carboxylate can bind to the zinc ion, prohibiting the nucleophilic attack of the zinc-bound hydroxide on the lactam carbonyl carbon. However, such a structure is energetically disfavored compared to the other enzyme-substrate complexes.
Originalsprog | Engelsk |
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Tidsskrift | The Journal of Physical Chemistry B |
Vol/bind | 108 |
Udgave nummer | 45 |
Sider (fra-til) | 17639-17648 |
Antal sider | 10 |
ISSN | 1520-6106 |
DOI | |
Status | Udgivet - 2004 |