a, b, Crystal packing of Y1R–UR-MK299 (a) and Y1R–BMS-193885 (b) complexes. Y1R is shown in cartoon representation and coloured brown and green in the Y1R–UR-MK299 and Y1R–BMS-193885 complexes, respectively. The T4L fusion is shown in grey cartoon representation. UR-MK299 and BMS-193885 are displayed as yellow and pink spheres, respectively. c, Cutaway view of the UR-MK299-binding pocket in Y1R. The receptor is shown in brown cartoon and surface representations. The ligand is shown as yellow sticks. d, Comparison of Y1R in the Y1R–UR-MK299 crystal structure (brown) and the Y1R–NPY model (green). Side chains of Q1203.32 and W2766.48 are shown as sticks. R35–Y36 of NPY is displayed as cyan sticks. The hydrogen bond between Q1203.32 and Y36 of NPY is shown as a green dashed line. e–j, Chemical structures of the argininamide Y1R antagonists BIBP3226 (e), UR-HU404 (f), UR-MK299 (g), BIBO3304 (h), UR-MK289 (i) and UR-MK136 (j). k, Chemical structure of BMS-193885. l, Scaffold of NPY C-terminal residues R35 and Y36. Key differences between R35–Y36 of NPY and UR-MK299 are chirality of the arginine derivative and alteration of bond connectivity leading to the hydroxyphenyl group.