Fig. 5: Mechanistic implication of ligand-free and G_s-coupled GLP-1R, GCGR and GIPR complex structures.

a Superimposition of inactive GLP-1R and GCGR structures shows an extracellular shutting conformation (yellow shadow) and intracellular closed conformation (gray shadow), thus intercepting peptide binding and G_s coupling. b Superimposition of ligand-free GLP-1R, GCGR and GIPR structures shows that G_s coupling directly causes the formation of an intracellular cavity and stabilizes the intracellular half of TMD, whereas the extracellular portion of the receptor is stabilized in the central and outer layers. c, d Magnified views of different contacting modes in the central (c) and outer (d) layers of GLP-1R, GCGR and GIPR. Key interacting residues are shown as ball-and-sticks, and the interactions are shown as dashed lines. e Superimposition of endogenous ligand-bound GLP-1R, GCGR and GIPR structures shows that peptide binding stabilizes the TM6–ECL3–TM7 conformation and rewires G_s protein. The right panel shows magnified views of the M/K^5.33b–R^5.40b–T/D/E^ECL3 and L^6.48b–Y^7.57b–N^7.61b–E^8.49b–E392^GαH5 interfaces. Key interacting residues are shown as ball-and-sticks. 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 e refers to N^8.47b in GPCRdb numbering.