ArticleNature communications2025
Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Engineering dextranase for the directed preparation of low-molecular-weight dextran.Food chemistry. Molecular sciences · 2026Article
- Transaminases engineering and their cascade systems for natural product synthesis.Applied biochemistry and biotechnology · 2026Review
- A functional missense variant iniScience · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Design of Safe and Efficient Adenine Base Editors via Protein Language Model Screening for Osteoarthritis Treatment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Semi-rational design of the N-terminal of Chondroitinase ABC to improve the catalytic activity.World journal of microbiology & biotechnology · 2026Article
- Temperature-Dependent Active-Site Rearrangements of PETaseSM14: Insights from Molecular Dynamics Simulations.International journal of molecular sciences · 2026Article
- Mapping functional dynamics hotspots for protein engineering with NMR peak intensity analysis.Protein engineering, design & selection : PEDS · 2026Article
- Integrated framework for targeting dynamic penicillin-binding protein 2a via ensemble structural biology and deep generative modeling.Frontiers in microbiology · 2026Article
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Abstract
The role of amino-acid residues distant from an enzyme's active site in facilitating the complete catalytic cycle-including substrate binding, chemical transformation, and product release-remains poorly understood. Here, we investigate how distal mutations promote the catalytic cycle by engineering mutants of three de novo Kemp eliminases containing either active-site or distal mutations identified through directed evolution. Kinetic analyses, X-ray crystallography, and molecular dynamics simulations reveal that while active-site mutations create preorganized catalytic sites for efficient chemical transformation, distal mutations enhance catalysis by facilitating substrate binding and product release through tuning structural dynamics to widen the active-site entrance and reorganize surface loops. These distinct contributions work together to improve overall activity, demonstrating that a well-organized active site, though necessary, is not sufficient for optimal catalysis. Our findings reveal critical roles that distal residues play in shaping the catalytic cycle to enhance efficiency, yielding valuable insights for enzyme design.
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