TY - JOUR
T1 - Crystallographic investigation of the inhibition mode of a VIM-2 metallo-β-lactamase from Pseudomonas aeruginosa by a mercaptocarboxylate inhibitor
AU - Yamaguchi, Yoshihiro
AU - Jin, Wanchun
AU - Matsunaga, Kazuyo
AU - Ikemizu, Shinnji
AU - Yamagata, Yuriko
AU - Wachino, Jun Ichi
AU - Shibata, Naohiro
AU - Arakawa, Yoshichika
AU - Kurosaki, Hiromasa
PY - 2007/12/27
Y1 - 2007/12/27
N2 - The VIM-2 metallo-β-lactamase enzyme from Pseudomonas aeruginosa catalyzes the hydrolysis of most β-lactam antibiotics including carbapenems, and there are currently no potent inhibitors of such enzymes. We found rac-2-ω-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 Å. 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 loopl near the active site, by π-π stacking interactions. The methylene group interacted with Phe61(42) located at the bottom of loopl through CH-π 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.
AB - The VIM-2 metallo-β-lactamase enzyme from Pseudomonas aeruginosa catalyzes the hydrolysis of most β-lactam antibiotics including carbapenems, and there are currently no potent inhibitors of such enzymes. We found rac-2-ω-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 Å. 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 loopl near the active site, by π-π stacking interactions. The methylene group interacted with Phe61(42) located at the bottom of loopl through CH-π 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.
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U2 - 10.1021/jm701031n
DO - 10.1021/jm701031n
M3 - Article
C2 - 18052313
AN - SCOPUS:37349001297
SN - 0022-2623
VL - 50
SP - 6647
EP - 6653
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 26
ER -