ArticleProceedings of the National Academy of Sciences of the United States of America2014
Protective hinge in insulin opens to enable its receptor engagement.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 182 citations in OpenAlex.
- Damping amyloid-associated conformational fluctuations in a protein by an engineered diselenide bridge.Protein science : a publication of the Protein Society · 2026Article
- Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.Nature communications · 2026Article
- Evolution of Insulin, Insulin-like Growth Factors, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses.Molecular biology and evolution · 2026Article
- Ultrastable Insulin-Glucagon Fusion Protein Exploits an Endogenous Hepatic Switch to Mitigate Hypoglycemic Risk.ACS pharmacology & translational science · 2025Article
- Stabilization of a protein by a single halogen-based aromatic amplifier.Protein science : a publication of the Protein Society · 2025Article
- Synthetic studies of the mutant proinsulin syndrome demonstrate correlation between folding efficiency and age of diabetes onset.International journal of peptide research and therapeutics · 2025Article
- State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.Aging and disease · 2024Review
- A λ-Dynamics Investigation of InsulinJournal of chemical information and modeling · 2024Article
- Clues to the Design of Aggregation-Resistant Insulin from Proline Scanning of Highly Amyloidogenic Peptides Derived from the N-Terminal Segment of the A-Chain.Molecular pharmaceutics · 2024Article
- A λ-dynamics investigation of insulinbioRxiv : the preprint server for biology · 2024Article
- Size matters: the biochemical logic of ligand type in endocrine crosstalk.Life metabolism · 2024Article
- FK506-Binding Protein 2 Participates in Proinsulin Folding.Biomolecules · 2023Article
- Article
- Single-chain insulin analogs threaded by the insulin receptor αCT domain.Biophysical journal · 2022Article
- Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity.ACS medicinal chemistry letters · 2022Article
- How insulin-like growth factor I binds to a hybrid insulin receptor type 1 insulin-like growth factor receptor.Structure (London, England : 1993) · 2022Article
- An Insulin Receptor-Binding Multifunctional Protein fromFoods (Basel, Switzerland) · 2022Article
- Unconventional insulins from predators and pathogens.Nature chemical biology · 2022Review
- Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager.Science translational medicine · 2022Article
- Symmetric and asymmetric receptor conformation continuum induced by a new insulin.Nature chemical biology · 2022Article
24 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
21 authors at 9 institutions in 5 countries.
Funding
Abstract
Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in β cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 β-turn, coupling reorientation of Phe(B24) to a 60° rotation of the B25-B28 β-strand away from the hormone core to lie antiparallel to the receptor's L1-β2 sheet. Opening of this hinge enables conserved nonpolar side chains (Ile(A2), Val(A3), Val(B12), Phe(B24), and Phe(B25)) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptor-bound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function.
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Registered trials
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