Investigating GIPR (Ant)Agonism: A Structural Analysis of GIP and Its Receptor

The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Rational design of ligands, however, has been tedious with no structural data of the GIP receptor available. This study investigates structure and function of the GIP receptor (GIPR), using a homology model based on the GLP-1 receptor. Molecular dynamics combined with in vitro mutational data were used to pinpoint residues that play a role in ligand binding and/or receptor activation. Significant differences in binding mode were identified for the naturally occurring agonists GIP(1-30)NH₂ and GIP(1-42) compared to high potency antagonists GIP(3-30)NH₂ and GIP(5-30)NH₂. Residues R183^2.60, R190^2.67 and R300^5.40 are shown to play a key role in the activation of the GIPR and evidence suggests that a disruption of the K293^ECL2 – E362^ECL3 salt bridge by GIPR antagonists strongly reduces GIPR activation. These findings improve the basis for rational design of ligands targeting the GIPR.