Fig. 3. Differential Ca²⁺ and ligand binding at TM3.

Superpositions of NDP-α-MSH (residues 4–11), setmelanotide, and SHU9119 bound at MC4R (orange, light-yellow, and gray backbone cartoons). a Superposition of both agonists. Residues that are shared by the agonists are labeled in pink. b, c The ligand-binding mode of SHU9119 is compared with NDP-α-MSH (b) and setmelanotide (c). Bi-directional red arrows indicate differences in the relative spatial positioning of residues, the TM3, or the Ca²⁺ ion. Detailed intermolecular interactions are summarized in Supplementary information, Tables S5 and S6. d The relative alterations of TM3 orientation are also found in Ca²⁺ and its interacting residues of the EDD motif.