ArticleNature communications2022
An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Deep learning insights into β-lactamase dynamics and resistance evolution.The Biochemical journal · 2026Review
- Molecular Dynamics-Instantaneous Frequencies of Molecules Method to Address the Performance of Classical and Rigid Water Force Fields.The journal of physical chemistry. B · 2026Article
- Mechanistic insights into phthalylsulfacetamide-induced restoration of meropenem bactericidal activity in NDM-1-positive Escherichia coli.BMC microbiology · 2026Article
- Challenges of Carbapenem-ResistantAntibiotics (Basel, Switzerland) · 2025Review
- Article
- Enzymolysis Modes Trigger Diversity in Inhibitor-α-Amylase Aggregating Behaviors and Activity Inhibition: A New Insight Into Enzyme Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Friends and relatives: insight into conformational regulation from orthologues and evolutionary lineages using KIF and KIN.Faraday discussions · 2024Article
- Drug Discovery in the Field of β-Lactams: An Academic Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- Mapping the determinants of catalysis and substrate specificity of the antibiotic resistance enzyme CTX-M β-lactamase.Communications biology · 2023Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
β-lactamases inactivate β-lactam antibiotics leading to drug resistance. Consequently, inhibitors of β-lactamases can combat this resistance, and the β-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor. The widespread CTX-M-14 and CTX-M-15 β-lactamases have an 83% sequence identity. In this study, we show that BLIP weakly inhibits CTX-M-14 but potently inhibits CTX-M-15. The structure of the BLIP/CTX-M-15 complex reveals that binding is associated with a conformational change of an active site loop of β-lactamase. Surprisingly, the loop structure in the complex is similar to that in a drug-resistant variant (N106S) of CTX-M-14. We hypothesized that the pre-established favorable loop conformation of the N106S mutant would facilitate binding. The N106S substitution results in a ~100- and 10-fold increase in BLIP inhibition potency for CTX-M-14 and CTX-M-15, respectively. Thus, this indicates that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility. These findings highlight the role of accessible active site conformations in controlling enzyme activity and inhibitor susceptibility as well as the influence of mutations in selectively stabilizing discrete conformations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.