ArticleJournal of the American Chemical Society2017
4S-Hydroxylation of Insulin at ProB28 Accelerates Hexamer Dissociation and Delays Fibrillation.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 47 citations in OpenAlex.
- Spatially constrained disulfide bond shuffling delays insulin aggregation and enhances neurotoxicity.Nature communications · 2025Article
- NMR-Derived Salt Bridges in Insulin Analogue: Resolving Artifactual Overbinding in Molecular Dynamics via Charge Scaling.The journal of physical chemistry letters · 2025Article
- Residue-Specific Incorporation of Noncanonical Amino Acids in Auxotrophic Hosts:Chemical reviews · 2025Review
- Synthesis of a highly thermostable insulin by phenylalanine conjugation at B29 Lysine.Communications chemistry · 2024Article
- Incorporation of Aliphatic Proline Residues into Recombinantly Produced Insulin.ACS chemical biology · 2023Article
- Structural basis of insulin fibrillation.Science advances · 2023Article
- FK506-Binding Protein 2 Participates in Proinsulin Folding.Biomolecules · 2023Article
- Stereoselective peptide catalysis in complex environments - from river water to cell lysates.Chemical science · 2022Article
- High-Throughput Aminoacyl-tRNA Synthetase Engineering for Genetic Code Expansion in Yeast.ACS synthetic biology · 2022Article
- Broadening the Toolkit for Quantitatively Evaluating Noncanonical Amino Acid Incorporation in Yeast.ACS synthetic biology · 2021Article
- Genetic Code Expansion in the Engineered Organism Vmax X2: High Yield and Exceptional Fidelity.ACS central science · 2021Article
- How To Quantify a Genetic Firewall? A Polarity-Based Metric for Genetic Code Engineering.Chembiochem : a European journal of chemical biology · 2021Article
- Incorporation of proline analogs into recombinant proteins expressed in Escherichia coli.Methods in enzymology · 2021Article
- Reporter system architecture affects measurements of noncanonical amino acid incorporation efficiency and fidelity.Molecular systems design & engineering · 2020Article
- Synthesis and Characterization of an A6-A11 Methylene Thioacetal Human Insulin Analogue with Enhanced Stability.Journal of medicinal chemistry · 2019Article
- Future prospects for noncanonical amino acids in biological therapeutics.Current opinion in biotechnology · 2019Review
- Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Daily injections of insulin provide lifesaving benefits to millions of diabetics. But currently available prandial insulins are suboptimal: The onset of action is delayed by slow dissociation of the insulin hexamer in the subcutaneous space, and insulin forms amyloid fibrils upon storage in solution. Here we show, through the use of noncanonical amino acid mutagenesis, that replacement of the proline residue at position 28 of the insulin B-chain (ProB28) by (4S)-hydroxyproline (Hzp) yields an active form of insulin that dissociates more rapidly, and fibrillates more slowly, than the wild-type protein. Crystal structures of dimeric and hexameric insulin preparations suggest that a hydrogen bond between the hydroxyl group of Hzp and a backbone amide carbonyl positioned across the dimer interface may be responsible for the altered behavior. The effects of hydroxylation are stereospecific; replacement of ProB28 by (4R)-hydroxyproline (Hyp) causes little change in the rates of fibrillation and hexamer disassociation. These results demonstrate a new approach that fuses the concepts of medicinal chemistry and protein design, and paves the way to further engineering of insulin and other therapeutic proteins.
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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.