The insulin signaling system plays a key role in cellular metabolism, growth, division, differentiation, and survival. Misregulation of signalling is implicated in three major disease states - Type 2 diabetes, cancer and  Alzheimer’s disease. The insulin system is complemented by the insulin-like growth factor signalling system - and cross-talk between these two system is now being understood as a major reason for failure of Phase III clinical trials of antibodies directed against the IGF-1R receptor alone. Understanding how ligands can cross-bind to these two receptor ectodomains is a key goal to our research. However, he structure of insulin in complex with its receptor has been elusive, as the receptor protein is highly glycosylated and disulphide-rich, making its production and crystallization both difficult and costly.

In this talk, we present structures of insulin in complex with domain-minimized versions of the receptor that are in turn complexed with an Fab module to overcome the hindrance posed to crystallization by the receptor glycans. The revealed mode of hormone molecular recognition is one of induced fit involving a long-postulated structural unfolding of insulin that is facilitated in part by a re-arrangement of the C-terminal helix of the receptor -chain. These structures also suggest how insulin might cross-link to a secondary binding site on the receptor surface and so activate the receptor via signal transduction across the cell membrane.