Nature, published online 10 January 2013; doi:10.1038/nature11781

Insulin signaling occurs via the insulin receptor (IR), which is a receptor tyrosine kinase and a key component of cellular metabolism, growth, division, differentiation and survival. Misregulation of signaling via IR is implicated in disorders such as type 2 diabetes and Alzheimer's disease. The costructure of insulin in complex with IR has been elusive owing to difficulties in producing the receptor protein, which contains numerous glycosylated residues and disulfide bonds. Menting et al. now solve four crystal structures of insulin bound to a truncated IR. A previous structure of the unliganded IR ectodomain, which showed a disulfide-linked dimer with a folded-over conformation, predicted two insulinbinding surfaces per receptor monomer, and the new structures show insulin bound to the primary site. The structures also confirm an induced-fit mechanism of molecular recognition and identify a remarkable feature, namely relocation of a C-terminal segment of the α-protomer (αCT) upon hormone binding. Cross-linking data derived from the intact IR, as well as mutational analyses combined with isothermal titration calorimetry, further confirm the observed insulin-IR interactions. The mode of receptor engagement the authors visualized is unique among receptor tyrosine kinases, and the structures suggest a mechanism for initiating downstream signals.