ArticleJournal of molecular biology2015
Negative Epistasis and Evolvability in TEM-1 β-Lactamase--The Thin Line between an Enzyme's Conformational Freedom and Disorder.
Article in Journal of molecular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
What it found
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Who cites it
75 citing papers in PubMed, 119 citations in OpenAlex.
- Advancements in Technologies Targeting Horizontal Gene TransferRoutes to Control Drug Resistance Evolution.ACS bio & med chem Au · 2026Review
- Mutation-biased adaptation is consequential even in large bacterial populations.Nature communications · 2026Article
- Molecular Engineering of Nicotinamide Riboside Kinase and Process Optimization for Efficient Nicotinamide Mononucleotide Production.Foods (Basel, Switzerland) · 2026Article
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Saturation mutagenesis map of generalist versus specialist adaptations of β-lactamase to novel antibiotics.bioRxiv : the preprint server for biology · 2026Article
- Molecular basis of ampicillin resistance: combinatorial mechanisms and future strategies.World journal of microbiology & biotechnology · 2026Review
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- Pathogenicity ofFrontiers in cellular and infection microbiology · 2026Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Molecular insights into the evolutionary trajectory of aAntimicrobial agents and chemotherapy · 2024Article
- Mutations Selectively Evolving Peroxidase Activity Among Alternative Catalytic Functions of Human Glutathione Transferase P1-1.Antioxidants (Basel, Switzerland) · 2024Article
- Friends and relatives: insight into conformational regulation from orthologues and evolutionary lineages using KIF and KIN.Faraday discussions · 2024Article
- Selection of a promiscuous minimalist cAMP phosphodiesterase from a library of de novo designed proteins.Nature chemistry · 2024Article
- Viral Receptor-Binding Protein Evolves New Function through Mutations That Cause Trimer Instability and Functional Heterogeneity.Molecular biology and evolution · 2024Article
- Rational design of a highly activeEngineering microbiology · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.Nature catalysis · 2024Article
- Bacteriophage Φ21's receptor-binding protein evolves new functions through destabilizing mutations that generate non-genetic phenotypic heterogeneity.Virus evolution · 2024Article
- Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis--a complete reversion of mutational effects, particularly in protein evolution--yet its molecular basis remains poorly understood. We describe the structural basis of sign epistasis between G238S and R164S, two adaptive mutations in TEM-1 β-lactamase--an enzyme that endows antibiotics resistance. Separated by 10 Å, these mutations initiate two separate trajectories toward increased hydrolysis rates and resistance toward second and third-generation cephalosporins antibiotics. Both mutations allow the enzyme's active site to adopt alternative conformations and accommodate the new antibiotics. By solving the corresponding set of crystal structures, we found that R164S causes local disorder whereas G238S induces discrete conformations. When combined, the mutations in 238 and 164 induce local disorder whereby nonproductive conformations that perturb the enzyme's catalytic preorganization dominate. Specifically, Asn170 that coordinates the deacylating water molecule is misaligned, in both the free form and the inhibitor-bound double mutant. This local disorder is not restored by stabilizing global suppressor mutations and thus leads to an evolutionary cul-de-sac. Conformational dynamism therefore underlines the reshaping potential of protein's structures and functions but also limits protein evolvability because of the fragility of the interactions networks that maintain protein structures.
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What OpenQuestion holds
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.