Fig. 2: General features of the ligand-free receptors by G_s coupling.

a–c Comparison of ligand-free and peptide-bound GLP-1R (a), GCGR (b) and GIPR (c) with inactive receptor structures reveals a similar G_s coupling interface in the absence or presence of an agonist. Black arrows show the movements of TM6 and H8 by indicating the distances of Cα atoms of T^6.42b, R^6.37b, and R/H^8.60b residues. d–f Structural comparison of the TMD bundles of GLP-1R (d), GCGR (e) and GIPR (f) indicates the requirement of G_s protein for receptor activation. Conformational changes are shown for the conserved HETY inactive motif (H^2.50b–E^3.50b–T^6.42b–Y^7.57b) and cytoplasmic polar network (R^2.46b–R^6.37b–N^7.61b–E^8.49b). Black arrows indicate the hallmark conformational changes of TM6. The Gβ and Gγ subunits are omitted for clarity. PDB IDs: 6LN2 (inactive GLP-1R), 5XEZ (inactive GCGR), 6X18 (GLP-1-bound GLP-1R), 6LMK (GCG-bound GCGR), and 7DTY (GIP-bound GIPR). The position of N^7.61b in d, e and f refers to N^8.47b in GPCRdb numbering.