4C09

Crystal structure of the metallo-beta-lactamase BCII

Summary for 4C09

• Entry DOI: 10.2210/pdb4c09/pdb
• Related: 4BZ3 4C1C 4C1D 4C1E 4C1F 4C1G 4C1H
• Descriptor: BETA-LACTAMASE 2, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, mbl, metallo-beta-lactamase, antibiotic resistance
• Biological source: BACILLUS CEREUS
• Cellular location: Periplasm : P04190
• Total number of polymer chains: 1
• Total formula weight: 25407.59

Authors

Zollman, D.,Brem, J.,McDonough, M.A.,van Berkel, S.S.,Schofield, C.J. (deposition date: 2013-07-31, release date: 2014-08-20, Last modification date: 2023-12-20)

Primary citation

Brem, J.,van Berkel, S.S.,Zollman, D.,Lee, S.Y.,Gileadi, O.,McHugh, P.J.,Walsh, T.R.,McDonough, M.A.,Schofield, C.J.
Structural Basis of Metallo-beta-Lactamase Inhibition by Captopril Stereoisomers.
Antimicrob. Agents Chemother., 60:142-150, 2015

PubMed Abstract: β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all β-lactam antibiotics, including recent-generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs. l-Captopril, which is used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the l- or d-captopril stereoisomer reveal correlations between the binding mode and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant Enterobacteriaceae and other organisms causing MBL-mediated resistant infections.

PubMed: 26482303
DOI: 10.1128/AAC.01335-15

Experimental method

X-RAY DIFFRACTION (1.2 Å)