(A) Comparison of the overall structures of GIP1-42–GIPR–Gs, GLP-1–GLP-1R–Gs (Zhang et al., 2020) and glucagon–GCGR–Gs complexes (Qiao et al., 2020). G proteins are omitted for clarity. (B–D) Close-up views of the interaction between TMD and peptide. Based on sequence similarity, the peptides are divided into four segments: N terminus (residues 1–3, B), segment 2 (residues 4–11, C), segment 3 (residues 12–20, D), and the C terminus (residues 21 to the end, E–G), where segments 2 and 4 are highly conserved among GIP, GLP-1, and glucagon. Residues are numbered based on GIP for peptides, and labeled with class B GPCR numbering in superscript for receptors (Wootten et al., 2013). (E–G) Close-up views of the interface between GIPR ECD and GIP C terminus (E), between GLP-1R and GLP-1 C terminus (F), and between GCGR and glucagon C terminus (G). The ECD is shown in surface representation and colored from dodger blue for the most hydrophilic region, to white, to orange red for the most hydrophobic region. (H) Comparison of peptide recognition modes for three receptors, described by fingerprint strings encoding different interaction types of the surrounding residues in each receptor. Peptide residue numbers on the top are shown based on GIP. The ligand-binding pocket residues that are identical or similar across three receptors are highlighted in dark gray and light gray, respectively. Color codes are listed on the bottom.