Once thought to be a unique capability of the Langerhans Islands in the pancreas of mammals, insulin production is now recognized as an evolutionarily ancient function going back to prokaryotes, ubiquitously present in unicellular eukaryotes, fungi, worm, Drosophila and of course human. While the functionality of the signaling pathway has been experimentally demonstrated in some of these organisms, it has not yet been exploited for pharmacological applications. To enable such applications, we need to understand the extent to which the structure and function of the insulin-insulin receptor system is conserved. To this end, we analyzed the insulin signaling pathway in corals through remote homology detection and modeling. By docking known insulin receptor ligands to a coral homology structure, we locate ligand binding pockets and demonstrate their conservation suggesting that it may be possible to exploit the structural conservation for pharmacological applications in non-model organisms. We also identified the coral homologues of the over 100 signaling proteins involved in insulin and its related signaling pathways, demonstrating their wide-spread conservation. Notable exceptions are glucagon and somatostatin. It is tempting to speculate that under high light conditions, when the algae synthetize excess sugars, the cnidarian host may experience insulin resistance, and that the cnidarian microbiome may be involved in manipulating the insulin signaling system.

The insulin receptor is a membrane protein responsible for regulation of nutrient balance and therefore an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms, (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor tyrosine kinase enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full-length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in-depth, structure-based review of human insulin receptor pharmacology in light of the new structures.