ArticleJournal of the American Chemical Society2012
Designing allosteric control into enzymes by chemical rescue of structure.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 54 citations in OpenAlex.
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- Origins of allostery in vertebrate hemoglobin evolution.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
- Article
- Review
- Allele-Specific Chemical Rescue of Histone Demethylases Using Abiotic Cofactors.ACS chemical biology · 2022Article
- Design and engineering of genetically encoded protein biosensors for small molecules.Current opinion in biotechnology · 2022Review
- Simple mechanisms for the evolution of protein complexity.Protein science : a publication of the Protein Society · 2022Review
- PLG-007 and Its Active Component Galactomannan-α Competitively Inhibit Enzymes That Hydrolyze Glucose Polymers.International journal of molecular sciences · 2022Article
- Advances in the Computational Design of Small-Molecule-Controlled Protein-Based Circuits for Synthetic Biology.Proceedings of the IEEE. Institute of Electrical and Electronics Engineers · 2022Article
- Controlling Enzymatic Activity by Modulating the Oligomerization State via Chemical Rescue and Optical Control.Chembiochem : a European journal of chemical biology · 2022Article
- De novo protein fold families expand the designable ligand binding site space.PLoS computational biology · 2021Article
- Computational Design of an Allosteric Antibody Switch by Deletion and Rescue of a Complex Structural Constellation.ACS central science · 2020Article
- Allostery in Its Many Disguises: From Theory to Applications.Structure (London, England : 1993) · 2019Review
- Converting a Periplasmic Binding Protein into a Synthetic Biosensing Switch through Domain Insertion.BioMed research international · 2019Review
- The Bump-and-Hole Tactic: Expanding the Scope of Chemical Genetics.Cell chemical biology · 2018Review
- Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Modulating Antibody Structure and Function through Directed Mutations and Chemical Rescue.ACS synthetic biology · 2018Article
- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Auxotrophy to Xeno-DNA: an exploration of combinatorial mechanisms for a high-fidelity biosafety system for synthetic biology applications.Journal of biological engineering · 2018Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Ligand-dependent activity has been engineered into enzymes for purposes ranging from controlling cell morphology to reprogramming cellular signaling pathways. Where these successes have typically fused a naturally allosteric domain to the enzyme of interest, here we instead demonstrate an approach for designing a de novo allosteric effector site directly into the catalytic domain of an enzyme. This approach is distinct from traditional chemical rescue of enzymes in that it relies on disruption and restoration of structure, rather than active site chemistry, as a means to achieve modulate function. We present two examples, W33G in a β-glycosidase enzyme (β-gly) and W492G in a β-glucuronidase enzyme (β-gluc), in which we engineer indole-dependent activity into enzymes by removing a buried tryptophan side chain that serves as a buttress for the active site architecture. In both cases, we observe a loss of function, and in both cases we find that the subsequent addition of indole can be used to restore activity. Through a detailed analysis of β-gly W33G kinetics, we demonstrate that this rescued enzyme is fully functionally equivalent to the corresponding wild-type enzyme. We then present the apo and indole-bound crystal structures of β-gly W33G, which together establish the structural basis for enzyme inactivation and rescue. Finally, we use this designed switch to modulate β-glycosidase activity in living cells using indole. Disruption and recovery of protein structure may represent a general technique for introducing allosteric control into enzymes, and thus may serve as a starting point for building a variety of bioswitches and sensors.
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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.