Structural basis for ligand recognition of incretin receptors.

The glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor are homologous G-protein-coupled receptors (GPCRs). Incretin receptor agonists stimulate the synthesis and secretion of insulin from pancreatic β-cells and are therefore promising agents for the treatment of type 2 diabetes. It is well established that the N-terminal extracellular domain (ECD) of incretin receptors is important for ligand binding and ligand specificity, whereas the transmembrane domain is involved in receptor activation. Structures of the ligand-bound ECD of incretin receptors have been solved recently by X-ray crystallography. The crystal structures reveal a similar fold of the ECD and a similar mechanism of ligand binding, where the ligand adopts an α-helical conformation. Residues in the C-terminal part of the ligand interact directly with the ECD and hydrophobic interactions appear to be the main driving force for ligand binding to the ECD of incretin receptors. Obviously, the-still missing-structures of full-length incretin receptors are required to construct a complete picture of receptor function at the molecular level. However, the progress made recently in structural analysis of the ECDs of incretin receptors and related GPCRs has shed new light on the process of ligand recognition and binding and provided a basis to disclose some of the mechanisms underlying receptor activation at high resolution.