To eat or not to eat
Melanocortin receptor 4 (MC4R) plays a role in regulating food intake: Its activation by a stimulating hormone inhibits appetite, whereas binding to a natural antagonist promotes appetite. Complementing a recent structure of MC4R in an inactive conformation, Israeli et al. present the structure bound to setmelanotide, a weight-control drug, and its G protein–signaling partner (see the Perspective by Farooqi). This work reveals the mechanism of MC4R activation and explains why setmelanotide acts as a potent agonist, whereas a structurally similar compound, SHU9119, is an inhibitor. The structure also provides insight into the contribution of mutations in MCR4 to weight-regulation disorders.
Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo–electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.