TY - JOUR

T1 - Investigating GIPR (ant)agonism

T2 - A structural analysis of GIP and its receptor

AU - Smit, Florent X.

AU - van der Velden, Wijnand J. C.

AU - Kizilkaya, Husun S.

AU - Nørskov, Amalie

AU - Lückmann, Michael

AU - Hansen, Tobias N.

AU - Sparre-Ulrich, Alexander H.

AU - Qvotrup, Katrine

AU - Frimurer, Thomas M.

AU - Rosenkilde, Mette M.

PY - 2021

Y1 - 2021

N2 - 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 R183(2.60), R190(2.67), and R300(5.40) are shown to be key for 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. Combinatorial use of these findings can benefit rational design of ligands targeting the GIPR.

AB - 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 R183(2.60), R190(2.67), and R300(5.40) are shown to be key for 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. Combinatorial use of these findings can benefit rational design of ligands targeting the GIPR.

KW - GASTRIC-INHIBITORY POLYPEPTIDE

KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE

KW - GLP-1 RECEPTOR

KW - GLUCOSE

KW - DYNAMICS

KW - GLUCAGON

KW - FAMILY

KW - FRAGMENT

KW - LESSONS

KW - COMPLEX

U2 - 10.1016/j.str.2021.04.001

DO - 10.1016/j.str.2021.04.001

M3 - Journal article

C2 - 33891864

VL - 29

SP - 679-693.e6

JO - Structure

JF - Structure

SN - 0969-2126

IS - 7

ER -