ArticleProceedings of the National Academy of Sciences of the United States of America2013
Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed.
- Programming local confinements in crystalline frameworks through reticular chemistry.Nature materials · 2026Article
- PRSS23 promotes ovarian cancer peritoneal dissemination independent of protease activity.The Journal of biological chemistry · 2026Article
- The Role of the Omega Subzone in Determining the Membership of a Protein in One of the Two Families of the LexA/Signal Peptidase-like Superfamily.International journal of molecular sciences · 2026Article
- Atom-level enzyme active site scaffolding using RFdiffusion2.Nature methods · 2026Article
- Language models reveal a complex sequence basis for adaptive convergent evolution of protein functions.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Alpha and Omega Classification of β-Lactamase/Transpeptidase-like Superfamily Proteins Based on the Comparison of Their Structural Catalytic Cores.Molecules (Basel, Switzerland) · 2025Article
- Computational design of serine hydrolases.Science (New York, N.Y.) · 2025Article
- Identifying and controlling inactive and active conformations of a serine protease.Science advances · 2025Article
- Evidence supporting a catalytic pentad mechanism for the proteasome and other N-terminal nucleophile enzymes.Nature communications · 2025Article
- Advances in the Search for SARS-CoV-2 MPathogens (Basel, Switzerland) · 2024Review
- Computational design of serine hydrolases.bioRxiv : the preprint server for biology · 2024Article
- Proton Transfer Kinetics in Histidine Side Chains Determined by pH-Dependent Multi-Nuclear NMR Relaxation.Journal of the American Chemical Society · 2024Article
- Noncanonical Amino Acids in Biocatalysis.Chemical reviews · 2024Review
- Structural insights into ubiquitin chain cleavage byLife science alliance · 2023Article
- The PNPLA family of enzymes: characterisation and biological role.Arhiv za higijenu rada i toksikologiju · 2023Article
- Review
- Minimalistic Artificial Catalysts with Esterase-Like Activity from Multivalent Nanofibers Formed by the Self-Assembly of Dipeptides.ACS omega · 2023Article
- The Nϵ-Rule for Serine, but Not Cysteine Catalytic Triads.Angewandte Chemie (International ed. in English) · 2022Article
- Transesterification of Non-Activated Esters Promoted by Small Molecules Mimicking the Active Site of Hydrolases.Angewandte Chemie (International ed. in English) · 2022Article
- Chitosan Graft Copolymers withPolymers · 2022Article
11 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
The study of proteolysis lies at the heart of our understanding of biocatalysis, enzyme evolution, and drug development. To understand the degree of natural variation in protease active sites, we systematically evaluated simple active site features from all serine, cysteine and threonine proteases of independent lineage. This convergent evolutionary analysis revealed several interrelated and previously unrecognized relationships. The reactive rotamer of the nucleophile determines which neighboring amide can be used in the local oxyanion hole. Each rotamer-oxyanion hole combination limits the location of the moiety facilitating proton transfer and, combined together, fixes the stereochemistry of catalysis. All proteases that use an acyl-enzyme mechanism naturally divide into two classes according to which face of the peptide substrate is attacked during catalysis. We show that each class is subject to unique structural constraints that have governed the convergent evolution of enzyme structure. Using this framework, we show that the γ-methyl of Thr causes an intrinsic steric clash that precludes its use as the nucleophile in the traditional catalytic triad. This constraint is released upon autoproteolysis and we propose a molecular basis for the increased enzymatic efficiency introduced by the γ-methyl of Thr. Finally, we identify several classes of natural products whose mode of action is sensitive to the division according to the face of attack identified here. This analysis of protease structure and function unifies 50 y of biocatalysis research, providing a framework for the continued study of enzyme evolution and the development of inhibitors with increased selectivity.
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