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Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP‐1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP‐1‐based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in‐depth molecular pharmacological phenotyping of GIPR‐[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1‐42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS‐7 cells revealing GIPR wt‐like affinities of GIP(1‐42) with K d values of ~2 nmol/L and wt‐like agonist association rates (K on). In contrast, the dissociation rates (K off) were slower, resulting in 25% higher agonist residence time for GIPR‐[E354Q]. Moreover, in Gαs signalling (cAMP production) GIP(1‐42) was ~2‐fold more potent and more efficacious on GIPR‐[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of β‐arrestin 2, whereas the agonist‐induced internalization rate was 2.1‐ to 2.3‐fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand‐binding kinetics will lead to receptor desensitization and down‐regulation. This could explain the long‐term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.