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Abstract
Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.
Highlights
The insulin receptor (IR) signaling system is a key regulator of metabolism and cellular growth
Purification of the recombinant protein directly from the medium resulted in a highly pure IR-ECD that was amenable to cryo-EM studies
1 C and S1 G), corresponding to a low-affinity binding regimen. This is in good agreement with the established concept that the soluble IR-ECD lacking membrane anchorage loses high-affinity binding in the picomolar range (Whittaker et al, 1994, 2008; Bass et al, 1996; Kiselyov et al, 2009; Subramanian et al, 2013; De Meyts, 2015), similar to the Epidermal growth factor (EGF) receptor ECD (Lax et al, 1991; Ferguson et al, 2003)
Summary
The insulin receptor (IR) signaling system is a key regulator of metabolism and cellular growth. The IR is an extensively glycosylated disulfide-linked (αβ) homodimer with a modular domain structure. Each protomer consists of an extracellular ligand-binding α subunit and the membranespanning β subunit, which harbors the intracellular kinase domain. The modular organization of the ectodomain (ECD) with high intrinsic flexibility poses a challenge to structural studies of the IR, as do the branched sugars of the glycosylation sites, and its complex ligand binding properties. Insulin binding to the ECD concomitantly elevates the receptor’s intrinsic tyrosine kinase activity before cellular signal transduction (Kasuga et al, 1982). The precise mechanism of how insulin initially engages its receptor, as well as the associated conformational changes leading to tyrosine kinase signaling, still remain elusive (De Meyts, 2015; Tatulian, 2015)
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