ArticleBiochemistry2016
Removal of the Side Chain at the Active-Site Serine by a Glycine Substitution Increases the Stability of a Wide Range of Serine β-Lactamases by Relieving Steric Strain.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Cysteine-mediated structural stabilization of the tetrameric GlpF.European biophysics journal : EBJ · 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
- A case of Baraitser-Winter cerebrofrontofacial syndrome diagnosed by whole-exome sequencing.Human genome variation · 2025Article
- Article
- SAND: a comprehensive annotation of class D β-lactamases using structural alignment-based numbering.Antimicrobial agents and chemotherapy · 2025Article
- Network of epistatic interactions in an enzyme active site revealed by large-scale deep mutational scanning.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Biofilm Lifestyle Shapes the Evolution of β-Lactamases.Genome biology and evolution · 2024Article
- Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress.Open biology · 2023Article
- Class C β-Lactamases: Molecular Characteristics.Clinical microbiology reviews · 2022Review
- Article
- Improve thermostability of Bacillus sp. TS chitosanase through structure-based alignment.Scientific reports · 2021Article
- Assessing the Potency of β-Lactamase Inhibitors with Diverse Inactivation Mechanisms against the PenA1 Carbapenemase fromACS infectious diseases · 2021Article
- Predicting the viability of beta-lactamase: How folding and binding free energies correlate with beta-lactamase fitness.PloS one · 2020Article
- Structural Insights into the Mechanism of Carbapenemase Activity of the OXA-48 β-Lactamase.Antimicrobial agents and chemotherapy · 2019Article
- Article
- Structure, activity and thermostability investigations of OXA-163, OXA-181 and OXA-245 using biochemical analysis, crystal structures and differential scanning calorimetry analysis.Acta crystallographica. Section F, Structural biology communications · 2017Article
- Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c).Biochemistry · 2017Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Serine β-lactamases are bacterial enzymes that hydrolyze β-lactam antibiotics. They utilize an active-site serine residue as a nucleophile, forming an acyl-enzyme intermediate during hydrolysis. In this study, thermal denaturation experiments as well as X-ray crystallography were performed to test the effect of substitution of the catalytic serine with glycine on protein stability in serine β-lactamases. Six different enzymes comprising representatives from each of the three classes of serine β-lactamases were examined, including TEM-1, CTX-M-14, and KPC-2 of class A, P99 of class C, and OXA-48 and OXA-163 of class D. For each enzyme, the wild type and a serine-to-glycine mutant were evaluated for stability. The glycine mutants all exhibited enhanced thermostability compared to that of the wild type. In contrast, alanine substitutions of the catalytic serine in TEM-1, OXA-48, and OXA-163 did not alter stability, suggesting removal of the Cβ atom is key to the stability increase associated with the glycine mutants. The X-ray crystal structures of P99 S64G, OXA-48 S70G and S70A, and OXA-163 S70G suggest that removal of the side chain of the catalytic serine releases steric strain to improve enzyme stability. Additionally, analysis of the torsion angles at the nucleophile position indicates that the glycine mutants exhibit improved distance and angular parameters of the intrahelical hydrogen bond network compared to those of the wild-type enzymes, which is also consistent with increased stability. The increased stability of the mutants indicates that the enzyme pays a price in stability for the presence of a side chain at the catalytic serine position but that the cost is necessary in that removal of the serine drastically impairs function. These findings support the stability-function hypothesis, which states that active-site residues are optimized for substrate binding and catalysis but that the requirements for catalysis are often not consistent with the requirements for optimal stability.
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