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| Title | Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2. |
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| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Jun 9, 2026 |
 Authors | Amber Vogel / Alan Blakely / Yuankun Dao / Nai-Pin Lin / Danny Chou / Christopher P Hill /  |
| PubMed Abstract | Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which ...Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism. |
 External links | Nat Commun / PubMed:42265100 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.64 - 3.89 Å |
| Structure data | EMDB-71877, PDB-9puv: EMDB-71878, PDB-9puw: EMDB-71894, PDB-9pvo: |
| Source |
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 Keywords | MEMBRANE PROTEIN / Antagonist / receptor tyrosine kinase / Antagonism |
homo sapiens (human)
phage #d (virus)