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. Limited structural data of its receptor has made ligand design tedious. This study investigates the 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 involved 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 with high potency antagonists GIP(3-30)NH2 and GIP(5-30)NH2. Residues R1832.60, R1902.67, and R3005.40 are shown to be key for activation of the GIPR, and evidence suggests that a disruption of the K293ECL2-E362ECL3 salt bridge by GIPR antagonists strongly reduces GIPR activation. Combinatorial use of these findings can benefit rational design of ligands targeting the GIPR. [Display omitted] •A complete mapping of GIP's distinct binding profile is presented•R1832.60, R1902.67, and R3005.40 likely play a key role in the activation of the GIPR•Disruption of the K293ECL2-E362ECL3 salt bridge could suppress GIPR activation•GIPR antagonists' action relies on a multifaceted inhibition of the receptor Smit et al. look at the relation between the structure and function of GIP and its receptor; proteins involved in energy expenditure and fat deposition. By pointing out residues that play a role in activation or debilitation of the receptor, Smit et al. hope to advance drug design efforts.