How Distinct Hormones Sculpt a Common Receptor: Ligand-Specific Conformational Pathways of the Insulin Receptor

• Cryo-EM structures reveal that insulin, IGF-I, and IGF-II all induce a similar T-shaped active IR conformation, but via distinct conformational pathways. • Insulin rapidly locks the receptor into a rigid, symmetric state, minimizing heterogeneity and promoting fast, synchronized signaling. • IGFs favor asymmetric, flexible intermediate states, enabling sustained and adaptable activation suited to growth and differentiation. • Ligand-specific engagement of binding sites 1 and 2 underlies differential cooperativity and signaling bias, with implications for therapeutic targeting.