ArticleJournal of the American Chemical Society2023
Design of Heme Enzymes with a Tunable Substrate Binding Pocket Adjacent to an Open Metal Coordination Site.
Article in Journal of the American Chemical Society, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 74 citations in OpenAlex.
- Design-Evolution Synergy Enables New-to-Nature Enzyme Chemistry.bioRxiv : the preprint server for biology · 2026Article
- Artificial metalloenzymes in complex biological environments.Nature chemical biology · 2026Review
- Engineering Metal-Pocket Cooperativity in Single-Atom COF Nanozymes for Selective Cascade Catalysis.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Less is more: miniaturized heme enzymes with broad reactivity.Chemical science · 2026Review
- Engineered Protein-Based Ionic Conductors for Sustainable Energy Storage Applications.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Deciphering the evolutionary origin of the enantioselectivity of short-chain dehydrogenases from plants toward 1-borneol.Nature communications · 2026Article
- A Review of Plant-Derived Diterpenoid Biosynthesis: From Structural Scaffold Diversity and Lineage-Associated Distribution to Enzyme Mining and Discovery Strategies.Molecules (Basel, Switzerland) · 2026Review
- The Expanding Reactivity of Cobamide-Containing Proteins: From Mechanistic Understanding to Non-native Biocatalysis.ACS catalysis · 2026Article
- De Novo Design of Near-Infrared Fluorescence-Activating Proteins.Journal of the American Chemical Society · 2026Article
- Tools For Building Artificial Biological Nanostructures.ACS nano · 2026Review
- Probing anion recognition in a cobalt(II) de novo designed metalloprotein.Journal of inorganic biochemistry · 2026Article
- Computational redesign and directed evolution of a lanthanide-dependent photoredox enzyme for enantioselective diol cleavage.Chemical science · 2026Article
- Review
- PCA-Based Database Mining Enables the Discovery of Bacterial Carbene Transferases for Stereodivergent Cyclopropanation.Angewandte Chemie (International ed. in English) · 2026Article
- Computational design of generalist cyclopropanases with stereodivergent selectivity.Nature communications · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Article
- Modeling protein-small molecule conformational ensembles with PLACER.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Porphyrins as cofactors in enzyme-catalyzed organic reactions.Biophysics reports · 2025Article
- Mechanistic Elucidation and Stereochemical Consequences of Alternative Binding of Alkenyl Substrates by Engineered Arylmalonate Decarboxylase.Journal of the American Chemical Society · 2025Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The catalytic versatility of pentacoordinated iron is highlighted by the broad range of natural and engineered activities of heme enzymes such as cytochrome P450s, which position a porphyrin cofactor coordinating a central iron atom below an open substrate binding pocket. This catalytic prowess has inspired efforts to design de novo helical bundle scaffolds that bind porphyrin cofactors. However, such designs lack the large open substrate binding pocket of P450s, and hence, the range of chemical transformations accessible is limited. Here, with the goal of combining the advantages of the P450 catalytic site geometry with the almost unlimited customizability of de novo protein design, we design a high-affinity heme-binding protein, dnHEM1, with an axial histidine ligand, a vacant coordination site for generating reactive intermediates, and a tunable distal pocket for substrate binding. A 1.6 Å X-ray crystal structure of dnHEM1 reveals excellent agreement to the design model with key features programmed as intended. The incorporation of distal pocket substitutions converted dnHEM1 into a proficient peroxidase with a stable neutral ferryl intermediate. In parallel, dnHEM1 was redesigned to generate enantiocomplementary carbene transferases for styrene cyclopropanation (up to 93% isolated yield, 5000 turnovers, 97:3 e.r.) by reconfiguring the distal pocket to accommodate calculated transition state models. Our approach now enables the custom design of enzymes containing cofactors adjacent to binding pockets with an almost unlimited variety of shapes and functionalities.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.