ArticleNature structural & molecular biology2022
Synergistic activation of the insulin receptor via two distinct sites.
Article in Nature structural & molecular biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 66 citations in OpenAlex.
- Insulin mimetics and non-canonical insulin receptor signaling: mechanisms and disease relevance.Experimental & molecular medicine · 2026Review
- Insulin resistance in the 21st century: new takes on an old problem-2025 Diabetes, Diabetes Care, and Diabetologia Expert Forum.Diabetologia · 2026Review
- Insulin-like growth factor-binding protein 7 is a soluble cell adhesion molecule.Science advances · 2026Article
- Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.Nature communications · 2026Article
- Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance.bioRxiv : the preprint server for biology · 2026Article
- Direct Selection of Functional De Novo Macrocycles for Activation of On-Cellulo Insulin Receptor.Angewandte Chemie (International ed. in English) · 2026Article
- Insulin resistance: mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- De novo protein design: a transformative frontier in clinical protein applications.Journal of translational medicine · 2026Review
- Influence and treatment of insulin receptor substrate/PI3K/Akt‑mediated insulin resistance in diabetes mellitus (Review).Molecular medicine reports · 2026Review
- Evolution of Insulin, Insulin-like Growth Factors, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses.Molecular biology and evolution · 2026Article
- Tuning insulin receptor signaling using de novo-designed agonists.Molecular cell · 2025Article
- Structure and activation of the Drosophila insulin receptor by three Drosophila insulin-like peptides.Nature communications · 2025Article
- Regulation and function of insulin and insulin-like growth factor receptor signalling.Nature reviews. Molecular cell biology · 2025Review
- Structural mechanism of insulin receptor activation by a dimeric aptamer agonist.Experimental & molecular medicine · 2025Article
- Multiscale Computational Protocols for Accurate Residue Interactions at the Flexible Insulin-Receptor Interface.Journal of chemical information and modeling · 2025Article
- FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology.Cell metabolism · 2025Article
- The use of intuitive AF-based modelling for the understanding of activation and signalling through insulin-like receptors.Frontiers in endocrinology · 2025Review
- A rare homozygousBMJ open diabetes research & care · 2024Article
- Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.Biochemistry · 2024Article
- Spontaneous Dimerization and Distinct Packing Modes of Transmembrane Domains in Receptor Tyrosine Kinases.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.
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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.