Fig. 6: Binding modes of agonist and antagonist ligands to MC4R.

a–d Sphere representations of setmelanotide (green, 7PIU), α-MSH (orange, 7F53), pN162 (cyan, 8QJ2), and SHU9119 (light blue, 6W25) in their respective MC4R binding sites (pink, blue, purple and gray, respectively). The horizontal dashed blue line across panels a-d shows the maximum depth reached by all ligands. e–h Side view of the main interactions of each ligand with their respective receptor. Only residue sidechains within 4 Å distance in the respective MC4R-ligand interfaces are shown; dashed lines represent Ca²⁺ coordination and hydrogen bonds. The blue dashed line represents the same height as in (a–d). The orange shaded circle in (d, h) highlights the deep interaction of D-Nal4 from the antagonist SHU9119 that forces L133^3.36 into the inactive state conformation (see active-inactive state overlay Supplementary Fig. 6a). Top view of the key interactions involved in Ca²⁺ binding (i, j, l) and the position of pN162 CDR3 R101 residue sidechain (k) occupying the Ca²⁺ space in the binding pocket. For pN162 only CDR3 interactions are shown. For CDR1-TM7 and framework interaction with ECL3, see Supplementary Fig. 7b, d, respectively. Where highlighted, individual atom colors follow the standard CPK rules (red = oxygen, blue = nitrogen, yellow = sulfur).