ArticleACS catalysis2018
Conformational Intermediate That Controls KPC-2 Catalysis and Beta-Lactam Drug Resistance.
Article in ACS catalysis, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Genomic evolution and dissemination of non-conjugative virulence plasmid of ST65 carbapenem-resistant and hypervirulentFrontiers in cellular and infection microbiology · 2025Article
- Comparison of three colloidal gold immunoassays and GeneXpert Carba-R for the detection ofJournal of clinical microbiology · 2024Article
- Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.ACS infectious diseases · 2024Article
- Drug Discovery in the Field of β-Lactams: An Academic Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- Loop dynamics and the evolution of enzyme activity.Nature reviews. Chemistry · 2023Review
- Unveiling the structural features that regulate carbapenem deacylation in KPC-2 through QM/MM and interpretable machine learning.Physical chemistry chemical physics : PCCP · 2023Article
- Article
- QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A β-Lactamases.ACS infectious diseases · 2022Article
- Article
- The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability.International journal of molecular sciences · 2021Article
- The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases.Frontiers in microbiology · 2021Article
- Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?Antibiotics (Basel, Switzerland) · 2020Review
- Harnessing Conformational Plasticity to Generate Designer Enzymes.Journal of the American Chemical Society · 2020Review
- Biosynthetic Incorporation of Site-Specific Isotopes in β-Lactam Antibiotics Enables Biophysical Studies.ACS chemical biology · 2020Article
- Influence of substrates and inhibitors on the structure ofExperimental biology and medicine (Maywood, N.J.) · 2019Review
- β-Lactamases and β-Lactamase Inhibitors in the 21st Century.Journal of molecular biology · 2019Review
- Adaptive ensemble simulations of biomolecules.Current opinion in structural biology · 2018Review
- Predicting allostery and microbial drug resistance with molecular simulations.Current opinion in structural biology · 2018Review
- KPC-2 β-lactamase enables carbapenem antibiotic resistance through fast deacylation of the covalent intermediate.The Journal of biological chemistryArticle
- Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
The KPC-2 carbapenemase enzyme is responsible for drug resistance in the majority of carbapenem-resistant gram-negative bacterial infections in the United States. A better understanding of what permits KPC-2 to hydrolyze carbapenem antibiotics and how this might be inhibited is thus of fundamental interest and great practical importance to development of better anti-infectives. By correlating molecular dynamics simulations with experimental enzyme kinetics, we have identified conformational changes that control KPC-2's ability to hydrolyze carbapenem antibiotics. Related beta-lactamase enzymes can interconvert between catalytically permissive and catalytically nonpermissive forms of an acylenzyme intermediate critical to drug hydrolysis. Using molecular dynamics simulations, we identify a similar equilibrium in KPC-2 and analyze the determinants of this conformational change. Because the conformational dynamics of KPC-2 are complex and sensitive to allosteric changes, we develop an information-theoretic approach to identify key determinants of this change. We measure unbiased estimators of the reaction coordinate between catalytically permissive and nonpermissive states, perform information-theoretic feature selection and, using restrained molecular dynamics simulations, validate the protein conformational changes predicted to control catalytically permissive geometry. We identify two binding-pocket residues that control the conformational transitions between catalytically active and inactive forms of KPC-2. Mutations to one of these residues, Trp105, lower the stability of the catalytically permissive state in simulations and have reduced experimental
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Registered trials
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.