Investigating GIPR (ant)agonism: A structural analysis of GIP and its receptor

Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

“…The residue R190 is placed in the second transmembrane (TM2) domain in position 67 of the GIPR, hence denoted R190 2.67 (Wooten nomenclature in superscript; Wootten et al, 2013 ), near the first extracellular loop (ECL1), whereas E288 residue is located in the second extracellular loop (ECL2) of the receptor ( Figure 1A ). It has previously been shown that the N-terminal part of GIP, interacts with R190 2.67 by forming a hydrogen bond ( Smit et al, 2021 ; Zhao et al, 2021 ).…”

“…While several structure models exist for the closely related class B1 receptors, GLP-1R and glucagon receptor ( Zhang et al, 2017 , 2018 ), the structural data of the full length human GIPR are scarce, and only few studies have been conducted to describe GIPR residues of importance for receptor activation ( Yaqub et al, 2010 ; Cordomí et al, 2015 ). However, the importance of the R190- and E288 residues for GIP binding and GIPR activation was recently discussed in a study that combined MD simulations and mutagenesis experiments ( Smit et al, 2021 ). Here, it was shown that R190 is an important residue for GIPR activation as the N-terminal part of the GIP was described to form a hydrogen bond with this residue.…”

“…Moreover, a recent cryo-EM structure by Zhao et al (2021) of the human GIPR in complex with GIP and a G s -heterotrimer confirmed the formation of hydrogen bond between GIP and the R190 residue. The E288 residue appears to have a bigger impact on ligand binding (5.4-fold reduction in affinity and a B max of 32% compared to wild-type) than on activation, when substituted with an alanine ( Smit et al, 2021 ). This is in line with the results of the present study, as we also saw a limited maximum binding capacity of 13% in E288Q, as we would expect a mutation to glycine (in E288G) to remove all functionality like alanine does (in E288A).…”

Novel agonist and antagonist radioligands for the GLP‐2 receptor. Useful tools for studies of basic GLP‐2 receptor pharmacology

“…GPCRs combined with mutation studies have enabled the analysis of the active, intermediate and inactive conformations of the receptors, thereby revealing residues that are essential for ligand binding and/or activation (Smit et al, 2021;Sun et al, 2020;Zhang et al, 2017).…”

“…The GLP‐2 receptor is a G protein‐coupled receptor (GPCR), belonging to the subclass B1 of the GPCR family, which comprises 15 receptors including the GLP‐1 receptor the GIP receptor, the glucagon receptor, the secretin receptor and the vasoactive intestinal peptide 1 and 2 receptors (VPAC 1 and VPAC 2 ) (Fredriksson et al, 2003). High resolution structures of class B1 GPCRs combined with mutation studies have enabled the analysis of the active, intermediate and inactive conformations of the receptors, thereby revealing residues that are essential for ligand binding and/or activation (Smit et al, 2021; Sun et al, 2020; Zhang et al, 2017).…”