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The alpha subunits make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a <scene name='83/832953/Alpha_c_helix/6'>C-Terminal alpha helix</scene>(Figure 1). <ref name="Scapin"> PMID 29512653 </ref> The CT-alpha helix is unique in its position that allows it to reach across the receptor and interact with the insulin at the binding site on the opposing side of the receptor. The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/1'>cysteine residues</scene> at the CYS524 position on each alpha subunit. The disulfide bonds are important to the overall stabilization of the molecule has it binds to insulin. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/15'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/12'>sites 2 and 2'</scene> (Figure 2). The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity than that of sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly. <ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> Cryo-EM has imaged insulin bound structures that displayed a T-shape conformation in the alpha subunits, which make up the receptors extracellular domain region.<ref name="Uchikawa" />  

For insulin binding to induce the activation of the receptor and change its conformation to the active T state, binding at sites 1 and 1', as well as one insulin to either binding site 2 or 2', is required <ref name= "Uchikawa" />. Although interactions at all four binding sites are highly hydrophobic, the ligand binding interactions at sites 1 and 1' are different than at sites 2 and 2'. Sites 1 and 1' are signified by interactions between <scene name='83/832953/Sites_1_and_1_prime_location/14'>PRO495, PHE497, ARG498</scene> residues from the FnIII-1 domain and particular residues on the insulin ligand, such as HIS5. They also have significant disulfide linkages that help maintain a compact binging site. At sites 2 and 2' the FnIII-1 region has <scene name='83/832953/Sites_2_and_2_prime_location/10'>both basic residues-ARG479, LYS484, ARG488, ARG554- and hydrophobic residues- LEU486, LEU552, and PRO537-</scene> interacting with numerous residues on the surface of the insulin ligand.