Insulin signaling controls metabolic homeostasis. Insulin receptor (IR) is a receptor tyrosine kinase (RTK) that plays essential roles in glucose metabolism and cell growth and comprises two copies of extracellular α- and β-subunits. The α-subunit and the N-terminal part of the β-subunit are on the extracellular side, and the β-subunit continues with a single transmembrane helix and C-terminal cytoplasmic domains that are targets of insulin-dependent phosphorylation in downstream signaling. The α-subunits are disulphide linked to each other and to their respective β-subunit, and they form a large ectodomain comprising several subdomains (L1, CR, L2, FnIII (1-3)). IR has two distinct insulin-binding sites with different affinities for insulin, termed sites 1 and 2. One insulin molecule binds to the primary site, which consists of the L1 domain of one IR protomer and the C-terminal helix of the α chain (α-CT) of the other, site 1. The second insulin molecule is bound to the FnIII-1 domain, site 2. The ectodomain of the active IR/IR dimer adopts asymmetric conformations under non-saturating insulin concentrations in the dynamic range of 1-3 insulins bound. In first, site 2 acts as the initial insulin recruitment site, enabling insulin binding to site 1 at lower concentrations of insulin. In the next step, occupancy of a single site 1 in the two-protomer receptor is sufficient to induce assembly of the TM domains, and ultimately the cytoplasmic kinase domains, which eventually rearrange the IR/IR dimer into an active conformation. On the other hand, the fully saturated insulin receptor adopts symmetric conformation with 4 insulins bound, showing the difference in the conformation of the semi-saturated IR.