Academic Journal
Mutant protein chemical rescue: From mechanisms to therapeutics.
| Τίτλος: | Mutant protein chemical rescue: From mechanisms to therapeutics. |
|---|---|
| Συγγραφείς: | O'Meara TR; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Palanski BA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Chen M; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Qiao Y; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Cole PA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: pacole@bwh.harvard.edu. |
| Πηγή: | The Journal of biological chemistry [J Biol Chem] 2025 Apr; Vol. 301 (4), pp. 108417. Date of Electronic Publication: 2025 Mar 18. |
| Τύπος έκδοσης: | Journal Article; Review; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| Ιατρικοί όροι (MeSH): | Mutant Proteins*/genetics , Mutant Proteins*/chemistry , Mutant Proteins*/metabolism , Protein Engineering*/methods , Mutation*, Humans ; Protein Folding ; Animals ; Mutagenesis, Site-Directed |
| Περίληψη: | Chemical rescue is a technique for restoring the activity and/or structure of an engineered or naturally occurring (e.g., disease-associated) mutant protein by the introduction of a "molecular crutch" that abrogates the mutation's effect. This method was developed about 4 decades ago to facilitate mechanistic analysis of enzymes. Since then, a variety of purified proteins inactivated by site-directed mutagenesis have been successfully rescued by substrate moieties or exogenous small molecules, an approach that has continued to serve as an important tool for mechanistic enzymologists. More recently, chemical rescue has been applied to activate engineered proteins in intact biological systems for phenotypic and pathway-level analyses. There is growing interest in therapeutic applications of chemical rescue to correct protein mutations that give rise to human diseases. In this review, we first contextualize chemical rescue and discuss its utility in protein mechanistic analysis. Second, we review the advantages and caveats associated with using this approach to study protein function within biological settings. Third, we provide an overview of efforts to develop folding correctors that restore the proper function of disease-associated protein mutants. To conclude, future directions and challenges for the chemical rescue field are discussed. (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Conflicts of interest The authors declare that they do not have conflicts of interest with the contents of this article. |
| Grant Information: | R01 CA074305 United States CA NCI NIH HHS; F32 CA259214 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: cells; enzyme; mutation; small molecule; therapeutics |
| Substance Nomenclature: | 0 (Mutant Proteins) |
| Entry Date(s): | Date Created: 20250320 Date Completed: 20250515 Latest Revision: 20260307 |
| Update Code: | 20260307 |
| PubMed Central ID: | PMC12018205 |
| DOI: | 10.1016/j.jbc.2025.108417 |
| PMID: | 40113044 |
| Βάση Δεδομένων: | MEDLINE |
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