(A) Cartoon model of IR family activation. The IDs are shown as black lines in the ECDs, the disulfide linkages as black diamonds, phosphorylation as pink circles, activation loops as purple lines, ligand as green diamonds, and αCTs as cylinders. Surface representations and corresponding cartoon diagrams of (B) the ECD of unliganded-IR (PDB 3LOH; Smith et al., 2010), (C) insulin bound to the IR ECD fragment (PDB 3W14; Menting et al., 2013), or (D) a model of the entire IR ECD bound to two Insulin molecules. For each panel, one αβ subunit is colored white and the other orange, and Insulin green. Dashed lines outline the Fn2-3 domain tandems. The hinge point between F1 and Fn2-3 domains is indicated by black circles and cyan circles indicate the hinge point between CR and L2 domains.