ArticleJournal of the American Chemical Society2018
Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble.
Article in Journal of the American Chemical Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 102 citations in OpenAlex.
- Phage-assisted continuous evolution of enzymes for noncanonical tyrosine biosynthesis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Promiscuity-Guided Enzyme Evolution via Substrate Multiplexed Screening.Angewandte Chemie (International ed. in English) · 2026Review
- Functional conservation with mechanistic drift: AMP activation in the evolution of archaeal sugar kinases.Molecular biology and evolution · 2026Article
- Phage-assisted continuous evolution of enzymes for noncanonical tyrosine biosynthesis.bioRxiv : the preprint server for biology · 2026Article
- Artificial allosteric protein switches with machine-learning-designed receptors.Nature biotechnology · 2026Article
- Inactive but Essential: The Role of the Inactive State of E49 in the Mechanism of the Alpha Subunit of Tryptophan Synthase and Its Stand-Alone BlueprintACS catalysis · 2026Article
- Engaging Unstabilized Alkyl Radicals with Pyridoxal Radical Biocatalysis: Enantiodivergent Synthesis of Aliphatic Non-Canonical Amino Acids.bioRxiv : the preprint server for biology · 2026Article
- Single-Molecule DNA Tweezers Enable Programmable Control of Enzyme Activity via Arbitrary Molecular Cues.Angewandte Chemie (International ed. in English) · 2025Article
- Identification and understanding of allostery hotspots in proteins: Integration of deep mutational scanning and multi-faceted computational analyses.Journal of molecular biology · 2025Review
- Approaches for regulating enzyme activities: Recent advances in experiment and computation.Current opinion in structural biology · 2025Review
- A naturally occurring standalone TrpB enzyme provides insights into allosteric communication within tryptophan synthase.Protein science : a publication of the Protein Society · 2025Article
- Allostery and Evolution: A Molecular Journey Through the Structural and Dynamical Landscape of an Enzyme Super Family.Molecular biology and evolution · 2025Article
- Altering Active-Site Loop Dynamics Enhances Standalone Activity of the Tryptophan Synthase Alpha Subunit.ACS catalysis · 2024Article
- Continuous evolution of user-defined genes at 1 million times the genomic mutation rate.Science (New York, N.Y.) · 2024Article
- Harnessing conformational dynamics in enzyme catalysis to achieve nature-like catalytic efficiencies: the shortest path map tool for computational enzyme redesign.Faraday discussions · 2024Article
- Elucidation of the stereochemical mechanism of cystathionine γ-lyase reveals how substrate specificity constrains catalysis.ACS catalysis · 2024Article
- The β-subunit of tryptophan synthase is a latent tyrosine synthase.Nature chemical biology · 2024Article
- Ultrahigh Throughput Evolution of Tryptophan Synthase in Droplets via an Aptamer Sensor.ACS catalysis · 2024Article
- Temporal Resolution of Activity-Related Solvation Dynamics in the TIM Barrel Enzyme Murine Adenosine Deaminase.ACS catalysis · 2024Article
- Flexible active-site loops fine-tune substrate specificity of hyperthermophilic metallo-oxidases.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Allosteric enzymes contain a wealth of catalytic diversity that remains distinctly underutilized for biocatalysis. Tryptophan synthase is a model allosteric system and a valuable enzyme for the synthesis of noncanonical amino acids (ncAA). Previously, we evolved the β-subunit from Pyrococcus furiosus, PfTrpB, for ncAA synthase activity in the absence of its native partner protein PfTrpA. However, the precise mechanism by which mutation activated TrpB to afford a stand-alone catalyst remained enigmatic. Here, we show that directed evolution caused a gradual change in the rate-limiting step of the catalytic cycle. Concomitantly, the steady-state distribution of the intermediates shifts to favor covalently bound Trp adducts, which have increased thermodynamic stability. The biochemical properties of these evolved, stand-alone TrpBs converge on those induced in the native system by allosteric activation. High-resolution crystal structures of the wild-type enzyme, an intermediate in the lineage, and the final variant, encompassing five distinct chemical states, show that activating mutations have only minor structural effects on their immediate environment. Instead, mutation stabilizes the large-scale motion of a subdomain to favor an otherwise transiently populated closed conformational state. This increase in stability enabled the first structural description of Trp covalently bound in a catalytically active TrpB, confirming key features of catalysis. These data combine to show that sophisticated models of allostery are not a prerequisite to recapitulating its complex effects via directed evolution, opening the way to engineering stand-alone versions of diverse allosteric enzymes.
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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.