Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands

The paper investigates the structural basis for how bivalent insulin receptor ligands that bind both insulin receptor site 1 and site 2, specifically the antagonists S961 and Ins-AC-S2 (and contrasted with the agonist S597), inhibit or activate the insulin receptor. Using cryo-EM, the authors show that S961 and Ins-AC-S2 bind an inactive conformation of the insulin receptor, explaining their antagonism, and they identify that agonist versus antagonist activity depends on whether the site 1 and site 2 binding modules are presented in the site 1–site 2 versus site 2–site 1 order. They also report differences in binding mechanisms between S961 and Ins-AC-S2, including how each ligand displaces or engages the αCT region, and they describe a novel binding interface for Ins-AC-S2. The work explicitly notes its relevance to informing development of next-generation IR antagonists for congenital hyperinsulinism, but does not provide direct functional outcome limitations beyond the structural analysis. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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