Structural basis for the conformational changes of insulin receptor induced by three different hormone ligands

The insulin receptor (IR) is central to the regulation of glucose and lipid metabolism. Although insulin is its primary ligand, insulin-like growth factors I and II (IGF-I and IGF-II) also engage IR, albeit with reduced affinity. The structural basis of cooperative ligand binding, however, has remained poorly understood. Here, we report cryo-Electron Microscopy (cryo-EM) structures of IR in complex with insulin, IGF-I, and IGF-II, revealing that all three ligands engage the receptor at overlapping binding sites and can induce a conserved T-shaped quaternary assembly involving four ligand molecules at site 1/1' and site 2/2'. Despite this shared overall architecture, distinct ligand-specific conformational changes are observed. Notably, IGF-I and IGF-II adopt different binding sequence at site 1 and site 2 compared to insulin, suggesting unique interaction dynamics. These structural insights highlight divergent mechanisms of ligand recognition and cooperative binding, providing a deeper understanding of hormone-induced conformational modulation of the IR.