ArticlePLoS biology2016
Functional Sites Induce Long-Range Evolutionary Constraints in Enzymes.
Article in PLoS biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- Why structural divergence varies among residues in enzyme evolution: contributions of mutation, stability, and activity constraints.Molecular biology and evolution · 2026Article
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- Multiple molecular and cellular properties jointly affect protein and site-specific evolutionary rates.bioRxiv : the preprint server for biology · 2026Article
- Seven complete comparative maps of allosteric mutations in a protein family.Nature communications · 2026Article
- Site-Specific Structure and Stability Constrained Substitution Models Improve Phylogenetic Inference.Systematic biology · 2026Article
- The allosteric landscape of the Src kinase.Science advances · 2026Article
- Genes Encoding Intracellular Signaling Proteins in Animals Originated Along with Metazoa and Chordata: Chance or Necessity?Genome biology and evolution · 2025Article
- SCREEN: A Graph-based Contrastive Learning Tool to Infer Catalytic Residues and Assess Enzyme Mutations.Genomics, proteomics & bioinformatics · 2025Article
- Functional Optimization in Distinct Tissues and Conditions Constrains the Rate of Protein Evolution.Molecular biology and evolution · 2024Article
- Key interaction networks: Identifying evolutionarily conserved non-covalent interaction networks across protein families.Protein science : a publication of the Protein Society · 2024Article
- Substitution Models of Protein Evolution with Selection on Enzymatic Activity.Molecular biology and evolution · 2024Article
- Harnessing generative AI to decode enzyme catalysis and evolution for enhanced engineering.National science review · 2023Review
- Harnessing Generative AI to Decode Enzyme Catalysis and Evolution for Enhanced Engineering.bioRxiv : the preprint server for biology · 2023Article
- Discovering functionally important sites in proteins.Nature communications · 2023Article
- Catalytic Site Proximity Profiling for Functional Unification of Sequence-Diverse RadicalACS bio & med chem Au · 2023Article
- An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes.Molecular biology and evolution · 2023Article
- Structure-informed microbial population genetics elucidate selective pressures that shape protein evolution.Science advances · 2023Article
- Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022Review
- Ensemble origins and distance-dependence of long-range mutational effects in proteins.iScience · 2022Article
- Conserved coronavirus proteins as targets of broad-spectrum antivirals.Antiviral research · 2022Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Functional residues in proteins tend to be highly conserved over evolutionary time. However, to what extent functional sites impose evolutionary constraints on nearby or even more distant residues is not known. Here, we report pervasive conservation gradients toward catalytic residues in a dataset of 524 distinct enzymes: evolutionary conservation decreases approximately linearly with increasing distance to the nearest catalytic residue in the protein structure. This trend encompasses, on average, 80% of the residues in any enzyme, and it is independent of known structural constraints on protein evolution such as residue packing or solvent accessibility. Further, the trend exists in both monomeric and multimeric enzymes and irrespective of enzyme size and/or location of the active site in the enzyme structure. By contrast, sites in protein-protein interfaces, unlike catalytic residues, are only weakly conserved and induce only minor rate gradients. In aggregate, these observations show that functional sites, and in particular catalytic residues, induce long-range evolutionary constraints in enzymes.
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