ArticleJournal of molecular biology2010
Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM β-lactamases.
Article in Journal of molecular biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 85 citations in OpenAlex.
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Article
- Context-aware geometric deep learning for protein sequence design.Nature communications · 2024Article
- Noncanonical Amino Acids in Biocatalysis.Chemical reviews · 2024Review
- Structural and Dynamic Features of Acinetobacter baumannii OXA-66 β-Lactamase Explain Its Stability and Evolution of Novel Variants.Journal of molecular biology · 2024Article
- Antibiotic persistence and its impact on the environment.3 Biotech · 2023Review
- Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding.Nature communications · 2023Article
- Evolvability-enhancing mutations in the fitness landscapes of an RNA and a protein.Nature communications · 2023Article
- A dual gene-specific mutator system installs all transition mutations at similar frequencies in vivo.Nucleic acids research · 2023Article
- Experimental andACS infectious diseases · 2022Article
- Adaptive evolvability through direct selection instead of indirect, second-order selection.Journal of experimental zoology. Part B, Molecular and developmental evolution · 2022Review
- Klebsiella pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: an Evolutionary Overview.Antimicrobial agents and chemotherapy · 2022Review
- Mechanistic insights into global suppressors of protein folding defects.PLoS genetics · 2022Article
- Co-evolution of interacting proteins through non-contacting and non-specific mutations.Nature ecology & evolution · 2022Article
- The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases.ACS central science · 2021Article
- Genetic basis of molecular mechanisms in β-lactam resistant gram-negative bacteria.Microbial pathogenesis · 2021Review
- Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval.Microorganisms · 2021Article
- Mistranslation can promote the exploration of alternative evolutionary trajectories in enzyme evolution.Journal of evolutionary biology · 2021Article
- An in vivo selection system with tightly regulated gene expression enables directed evolution of highly efficient enzymes.Scientific reports · 2021Article
- Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The introduction of extended-spectrum cephalosporins and β-lactamase inhibitors has driven the evolution of extended-spectrum β-lactamases (ESBLs) that possess the ability to hydrolyze these drugs. The evolved TEM ESBLs from clinical isolates of bacteria often contain substitutions that occur in the active site and alter the catalytic properties of the enzyme to provide an increased hydrolysis of extended-spectrum cephalosporins or an increased resistance to inhibitors. These active-site substitutions often result in a cost in the form of reduced enzyme stability. The evolution of TEM ESBLs is facilitated by mutations that act as global suppressors of protein stability defects in that they allow the enzyme to absorb multiple amino acid changes despite incremental losses in stability associated with the substitutions. The best-studied example is the M182T substitution, which corrects protein stability defects and is commonly found in TEM ESBLs or inhibitor-resistant variants from clinical isolates. In this study, a genetic selection for second-site mutations that could partially restore function to a severely destabilized primary mutant enabled the identification of A184V, T265M, R275Q, and N276D, which are known to occur in TEM ESBLs from clinical isolates, as suppressors of TEM-1 protein stability defects. Further characterization demonstrated that these substitutions increased the thermal stability of TEM-1 and were able to correct the stability defects of two different sets of destabilizing mutations. The acquisition of compensatory global suppressors of stability costs associated with active-site mutations may be a common mechanism for the evolution of novel protein function.
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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.