Format

Send to

Choose Destination
See comment in PubMed Commons below
J Med Chem. 2007 Dec 27;50(26):6647-53. Epub 2007 Dec 6.

Crystallographic investigation of the inhibition mode of a VIM-2 metallo-beta-lactamase from Pseudomonas aeruginosa by a mercaptocarboxylate inhibitor.

Author information

1
Environmental Safety Center, Kumamoto University, Department of Structure-Function Physical Chemistry, Graduate School of Pharmaceutical Sciences, Japan. yyamagu@gpo.kumamoto-u.ac.jp

Abstract

The VIM-2 metallo-beta-lactamase enzyme from Pseudomonas aeruginosa catalyzes the hydrolysis of most beta-lactam antibiotics including carbapenems, and there are currently no potent inhibitors of such enzymes. We found rac-2-omega-phenylpropyl-3-mercaptopropionic acid, phenylC3SH, to be a potent inhibitor of VIM-2. The structure of the VIM-2-phenylC3SH complex was determined by X-ray crystallography to 2.3 A. The structure revealed that the thiol group of phenylC3SH bridged to the two zinc(II) ions and the phenyl group interacted with Tyr67(47) on loop1 near the active site, by pi-pi stacking interactions. The methylene group interacted with Phe61(42) located at the bottom of loop1 through CH-pi interactions. Dynamic movements were observed in Arg228(185) and Asn233(190) on loop2, compared with the native structure (PDB code: 1KO3 ). These results suggest that the above-mentioned four residues play important roles in the binding and recognition of inhibitors or substrates and in stabilizing a loop in the VIM-2 enzyme.

PMID:
18052313
DOI:
10.1021/jm701031n
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society
    Loading ...
    Support Center