ArticleNature chemical biology2014
Design of activated serine-containing catalytic triads with atomic-level accuracy.
Article in Nature chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
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- In Silico Analysis and Biochemical Characterization ofJournal of microbiology and biotechnology · 2024Article
- Computational design of serine hydrolases.bioRxiv : the preprint server for biology · 2024Article
- Noncanonical Amino Acids in Biocatalysis.Chemical reviews · 2024Review
- Mce1R of Mycobacterium tuberculosis prefers long-chain fatty acids as specific ligands: a computational study.Molecular diversity · 2023Article
- De Novo Computational Design of a Lipase with Hydrolysis Activity towards Middle-Chained Fatty Acid Esters.International journal of molecular sciences · 2023Article
- Activity-based protein profiling - finding general solutions to specific problems.Israel journal of chemistry · 2023Article
- Engineering enzyme activity using an expanded amino acid alphabet.Protein engineering, design & selection : PEDS · 2023Article
- Design and Characterization of In-One Protease-Esterase PluriZyme.International journal of molecular sciences · 2022Article
- The road to fully programmable protein catalysis.Nature · 2022Review
- Enzyme catalyzes ester bond synthesis and hydrolysis: The key step for sustainable usage of plastics.Frontiers in microbiology · 2022Review
- Perspectives on the Role of Enzymatic Biocatalysis for the Degradation of Plastic PET.International journal of molecular sciences · 2021Review
- Step-by-step design of proteins for small molecule interaction: A review on recent milestones.Protein science : a publication of the Protein Society · 2021Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
A challenge in the computational design of enzymes is that multiple properties, including substrate binding, transition state stabilization and product release, must be simultaneously optimized, and this has limited the absolute activity of successful designs. Here, we focus on a single critical property of many enzymes: the nucleophilicity of an active site residue that initiates catalysis. We design proteins with idealized serine-containing catalytic triads and assess their nucleophilicity directly in native biological systems using activity-based organophosphate probes. Crystal structures of the most successful designs show unprecedented agreement with computational models, including extensive hydrogen bonding networks between the catalytic triad (or quartet) residues, and mutagenesis experiments demonstrate that these networks are critical for serine activation and organophosphate reactivity. Following optimization by yeast display, the designs react with organophosphate probes at rates comparable to natural serine hydrolases. Co-crystal structures with diisopropyl fluorophosphate bound to the serine nucleophile suggest that the designs could provide the basis for a new class of organophosphate capture agents.
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