ArticleAntimicrobial agents and chemotherapy2019
The Reaction Mechanism of Metallo-β-Lactamases Is Tuned by the Conformation of an Active-Site Mobile Loop.
Article in Antimicrobial agents and chemotherapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- The global epidemiology and treatment of metallo-β-lactamase-producing gram-negative pathogens.JAC-antimicrobial resistance · 2026Review
- Crystal structure reveals the hydrophilic R1 group impairs NDM-1-ligand binding via water penetration at L3.Journal of structural biology: X · 2025Article
- Sustainable Joullié-Ugi and Continuous Flow Implementation Led to Novel Captopril-Inspired Broad-Spectrum Metallo-β-Lactamase Inhibitors.Journal of medicinal chemistry · 2025Article
- Active site loops of membrane-anchored metallo-β-lactamases from environmental bacteria determine cephalosporinase activity.Antimicrobial agents and chemotherapy · 2025Article
- Cefiderocol "under siege"? Understanding the rise of NDM-mediated resistance to novel agents.Chemical science · 2025Article
- Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes.Journal of medicinal chemistry · 2024Article
- Structural role of K224 in taniborbactam inhibition of NDM-1.Antimicrobial agents and chemotherapy · 2024Article
- Strategies to Name Metallo-β-Lactamases and Number Their Amino Acid Residues.Antibiotics (Basel, Switzerland) · 2023Review
- Structural Insights for β-Lactam Antibiotics.Biomolecules & therapeutics · 2023Review
- Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase.eLife · 2023Article
- The Characteristics of Extended-Spectrum β-Lactamases (ESBLs)-ProducingInfection and drug resistance · 2023Article
- Structural insights into the substrate specificity of IMP-6 and IMP-1 metallo-β-lactamases.Journal of biochemistry · 2022Article
- Localising individual atoms of tryptophan side chains in the metallo-Magnetic resonance (Gottingen, Germany) · 2022Article
- Exploring the Role of L10 Loop in New Delhi Metallo-β-lactamase (NDM-1): Kinetic and Dynamic Studies.Molecules (Basel, Switzerland) · 2021Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Bioinformatic analysis of subfamily-specific regions in 3D-structures of homologs to study functional diversity and conformational plasticity in protein superfamilies.Computational and structural biotechnology journal · 2021Article
- Structural Insights for Core Scaffold and Substrate Specificity of B1, B2, and B3 Metallo-β-Lactamases.Frontiers in microbiology · 2021Article
- Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?Antibiotics (Basel, Switzerland) · 2020Review
- Elusive structural changes of New Delhi metallo-β-lactamase revealed by ultraviolet photodissociation mass spectrometry.Chemical science · 2020Article
- Metallo-ß-lactamases: a review.Molecular biology reports · 2020Review
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Authors and funding
11 authors.
Funding
Abstract
Carbapenems are "last resort" β-lactam antibiotics used to treat serious and life-threatening health care-associated infections caused by multidrug-resistant Gram-negative bacteria. Unfortunately, the worldwide spread of genes coding for carbapenemases among these bacteria is threatening these life-saving drugs. Metallo-β-lactamases (MβLs) are the largest family of carbapenemases. These are Zn(II)-dependent hydrolases that are active against almost all β-lactam antibiotics. Their catalytic mechanism and the features driving substrate specificity have been matter of intense debate. The active sites of MβLs are flanked by two loops, one of which, loop L3, was shown to adopt different conformations upon substrate or inhibitor binding, and thus are expected to play a role in substrate recognition. However, the sequence heterogeneity observed in this loop in different MβLs has limited the generalizations about its role. Here, we report the engineering of different loops within the scaffold of the clinically relevant carbapenemase NDM-1. We found that the loop sequence dictates its conformation in the unbound form of the enzyme, eliciting different degrees of active-site exposure. However, these structural changes have a minor impact on the substrate profile. Instead, we report that the loop conformation determines the protonation rate of key reaction intermediates accumulated during the hydrolysis of different β-lactams in all MβLs. This study demonstrates the existence of a direct link between the conformation of this loop and the mechanistic features of the enzyme, bringing to light an unexplored function of active-site loops on MβLs.
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