9PVO

Novel site 1 interaction of the IR/Ins-AC-S2 complex

Summary for 9PVO

• Entry DOI: 10.2210/pdb9pvo/pdb
• EMDB information: 71894
• Descriptor: Isoform Long of Insulin receptor, Insulin chain A, Insulin chain B (3 entities in total)
• Functional Keywords: antagonism, receptor tyrosine kinase, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 227808.12

Authors

Vogel, A.,Blakely, A.,Hill, C.P. (deposition date: 2025-08-03, release date: 2026-06-10, Last modification date: 2026-06-24)

Primary citation

Vogel, A.,Blakely, A.,Dao, Y.,Lin, N.P.,Chou, D.,Hill, C.P.
Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Nat Commun, 17:-, 2026

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 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.

PubMed: 42265100
DOI: 10.1038/s41467-026-73851-1

Experimental method

ELECTRON MICROSCOPY (3.89 Å)