ArticleAntimicrobial agents and chemotherapy2012
Mutagenesis of zinc ligand residue Cys221 reveals plasticity in the IMP-1 metallo-β-lactamase active site.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- Quantum Chemical Insights into Antibiotic Structure-Activity Relationships and Mechanisms of Action: A Review.Molecules (Basel, Switzerland) · 2026Review
- Genetic diversity, biochemical properties, epidemiology, and detection methods of IMP- and VIM-type carbapenemases.Clinical microbiology reviews · 2025Review
- Immobilization of IMP-1 metallo-beta-lactamase on FeWater science and technology : a journal of the International Association on Water Pollution Research · 2022Article
- Metallo-β-lactamases and a tug-of-war for the available zinc at the host-pathogen interface.Current opinion in chemical biology · 2022Review
- A Novel Cooperative Metallo-β-Lactamase Fold Metallohydrolase from Pathogen Vibrio vulnificus Exhibits β-Lactam Antibiotic-Degrading Activities.Antimicrobial agents and chemotherapy · 2021Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Klebsiella pneumoniae Expressing VIM-1 Metallo-β-Lactamase Is Resensitized to Cefotaxime via Thiol-Mediated Zinc Chelation.Infection and immunity · 2019Article
- Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction.Nature neuroscience · 2019Article
- Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics.Nature communications · 2018Article
- Deep Sequencing of Random Mutant Libraries Reveals the Active Site of the Narrow Specificity CphA Metallo-β-Lactamase is Fragile to Mutations.Scientific reports · 2016Article
- B1-Metallo-β-Lactamases: Where Do We Stand?Current drug targets · 2016Review
- Biochemical characterization of New Delhi metallo-β-lactamase variants reveals differences in protein stability.The Journal of antimicrobial chemotherapy · 2015Article
- Understanding the determinants of substrate specificity in IMP family metallo-β-lactamases: the importance of residue 262.Protein science : a publication of the Protein Society · 2014Article
- An altered zinc-binding site confers resistance to a covalent inactivator of New Delhi metallo-beta-lactamase-1 (NDM-1) discovered by high-throughput screening.Bioorganic & medicinal chemistry · 2013Article
- Metallo-β-lactamase structure and function.Annals of the New York Academy of Sciences · 2013Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Metallo-β-lactamases catalyze the hydrolysis of a broad range of β-lactam antibiotics and are a concern for the spread of drug resistance. To analyze the determinants of enzyme structure and function, the sequence requirements for the subclass B1 IMP-1 β-lactamase zinc binding residue Cys221 were tested by saturation mutagenesis and evaluated for protein expression, as well as hydrolysis of β-lactam substrates. The results indicated that most substitutions at position 221 destabilized the enzyme. Only the enzymes containing C221D and C221G substitutions were expressed well in Escherichia coli and exhibited catalytic activity toward β-lactam antibiotics. Despite the lack of a metal-chelating group at position 221, the C221G enzyme exhibited high levels of catalytic activity in the presence of exogenous zinc. Molecular modeling suggests the glycine substitution is unique among substitutions in that the complete removal of the cysteine side chain allows space for a water molecule to replace the thiol and coordinate zinc at the Zn2 zinc binding site to restore function. Multiple methods were used to estimate the C221G Zn2 binding constant to be 17 to 43 μM. Studies of enzyme function in vivo in E. coli grown on minimal medium showed that both IMP-1 and the C221G mutant exhibited compromised activity when zinc availability was low. Finally, substitutions at residue 121, which is the IMP-1 equivalent of the subclass B3 zinc-chelating position, failed to rescue C221G function, suggesting the coordination schemes of subclasses B1 and B3 are not interchangeable.
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Registered trials
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