Document Type

Article

Language

eng

Format of Original

8 p.

Publication Date

6-2008

Publisher

American Chemical Society

Source Publication

Journal of the American Chemical Society

Source ISSN

0002-7863

Original Item ID

doi: 10.1021/ja0774562

Abstract

Metallo-β-lactamases are responsible for conferring antibiotic resistance on certain pathogenic bacteria. In consequence, the search for inhibitors that may be useful in combating antibiotic resistance has fueled much study of the active sites of these enzymes. There exists circumstantial evidence that the binding of substrates and inhibitors to metallo-β-lactamases may involve binding to the organic part of the molecule, in addition to or prior to binding to one or more active site metal ions. It has also been postulated that a conformational change may accompany this putative binding. In the present study, electron paramagnetic resonance spectrokinetic study of a spin-labeled variant of the class B2 metallo-β-lactamase ImiS identified movement of a component residue on a conserved α-helix in a catalytically competent time upon formation of a transient reaction intermediate with the substrate imipenem. In a significant subpopulation of ImiS, this conformational change was not associated with substrate binding to the active site metal ion but, rather, represents a distinct step in the reaction with ImiS. This observation has implications regarding the determinants of substrate specificity in metallo-β-lactamases and the design of potentially clinically useful inhibitors.

Comments

Accepted version. Journal of the American Chemical Society, Vol. 130, No. 26 (June 2008): 8215-8222. DOI. © American Chemical Society. Used with permission.

Brian Bennett was affiliated with Medical College of Wisconsin at the time of publication.

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