The melanocortin-4 receptor (MC4R),a hypothalamic master regulator of energy homeostasis and appetite,is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity.Here,we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA,the peptide agonists NDP-α-MSH and setmelanotide,with 2.9 (A) and 2.6 (A) resolution.Together with signaling data from structure-derived MC4R mutants,the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation.The ligand-binding modes of NDP-α-MSH,a high-affinity linear variant of the endogenous agonist α-MSH,and setmelanotide,a cyclic anti-obesity drug with biased signaling toward Gq/11,underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor.The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2,which also regulates the G-protein coupling profile of this promiscuous receptor.Finally,our structures reveal mechanistic details of MC4R activation/inhibition,and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.