ArticleScientific reports2016
High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 22 citations in OpenAlex.
- Light-Activated Metal-Dependent Protein Degradation: A Heterobifunctional Ruthenium(II) Photosensitizer Targeting New Delhi Metallo-β-lactamase 1.Journal of the American Chemical Society · 2025Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- A protein dynamics-based deep learning model enhances predictions of fitness and epistasis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Evolutionary Dynamics and Functional Differences in Clinically Relevant Pen β-Lactamases fromJournal of chemical information and modeling · 2025Article
- Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam.Nature communications · 2023Article
- Structure-function analysis ofeLife · 2023Article
- Inhibition of theACS infectious diseases · 2021Article
- KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam.Antimicrobial agents and chemotherapy · 2020Article
- Non-catalytic-Region Mutations Conferring Transition of Class A β-Lactamases Into ESBLs.Frontiers in molecular biosciences · 2020Article
- Predicting allostery and microbial drug resistance with molecular simulations.Current opinion in structural biology · 2018Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The omega loop in β-lactamases plays a pivotal role in substrate recognition and catalysis, and some mutations in this loop affect the adaptability of the enzymes to new antibiotics. Various mutations, including substitutions, deletions, and intragenic duplications resulting in tandem repeats (TRs), have been associated with β-lactamase substrate spectrum extension. TRs are unique among the mutations as they cause severe structural perturbations in the enzymes. We explored the process by which TRs are accommodated in order to test the adaptability of the omega loop. Structures of the mutant enzymes showed that the extra amino acid residues in the omega loop were freed outward from the enzyme, thereby maintaining the overall enzyme integrity. This structural adjustment was accompanied by disruptions of the internal α-helix and hydrogen bonds that originally maintained the conformation of the omega loop and the active site. Consequently, the mutant enzymes had a relaxed binding cavity, allowing for access of new substrates, which regrouped upon substrate binding in an induced-fit manner for subsequent hydrolytic reactions. Together, the data demonstrate that the design of the binding cavity, including the omega loop with its enormous adaptive capacity, is the foundation of the continuous evolution of β-lactamases against new drugs.
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