Fig. 5: MC4R receptor activation is mediated by TM3 and facilitated by TM6.
From: Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide
a Superposition of the agonist NDP-α-MSH (green/orange) and the antagonist SHU9119 (blue/gray) bound to MC4R. The supposed activation-pathway from the LBP to the Gs-protein interface is highlighted by green arrows and is triggered by ligand interactions at TM6, inducing the TM6 opening around W2586.48. Antagonistic action is facilitated by the interplay of d-Nal41 with L1333.36 (indicated by blue arrows) and a subsequently blocked “toggle switch” at W2586.48. b Top view on ligand pockets highlights (arrows) the relative positioning of transmembrane helices TM1–6 (antagonized versus active structures). c, d Comparison of active and antagonized MC4R structures. d Superposition of active NDP-α-MSH–MC4R and SHU9119–MC4R structures. Relative movements, at the CWxP6.50, P5.50(M)IF, N(D)P7.50xxY, and DR3.50Y motifs, that accompany the receptor activation are highlighted by black arrows. Key residues involved in receptor activation are shown as sticks.
