9CV3 | pdb_00009cv3

Mutation of an active site-adjacent residue in VIM indirectly dictates interactions with and blunts inhibition by D-captopril.

(2025) J Inorg Biochem 271: 112975-112975

• PubMed: 40513263 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1016/j.jinorgbio.2025.112975
• Primary Citation of Related Structures:  
  9CV1, 9CV2, 9CV3, 9CV4, 9CV5


• PubMed Abstract: 
  

  Activity assays and X-ray crystallographic studies were undertaken to elucidate the inhibitory mechanism of captopril stereoisomers on Verona integron-encoded metallo-β-lactamases, specifically VIM-20, VIM-31, and VIM-15. All three VIM-2-like variants (VIM-20, VIM-31, and VIM-15) and VIM-2 expressed in Escherichia coli exhibited catalytic activity with comparable steady-state kinetic parameters. Among the tested thiol drugs (L- and D-captopril, D,L-thiorphan, and 2,3-dimercaprol), IC ₅₀ analyses indicated that D-captopril and 2,3-dimercaprol were more potent inhibitors against the VIM enzymes examined in this study. Notably, the IC ₅₀ value of D-captopril against VIM-31 was an exception, closely resembling that of L-captopril. To elucidate this exceptional inhibitory potency of D-captopril and its binding mode in the active site of VIM-31, high-resolution crystal structures of VIM-20, VIM-31, and VIM-15 in complex with both L- and D-captopril are reported. These findings will help evaluate whether the identified potent inhibitor D-captopril could be further developed as a pan inhibitor targeting the VIM-family enzymes.

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Organizational Affiliation: 

Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA.