Research Article

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

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Science  21 May 2021:
Vol. 372, Issue 6544, pp. 808-814
DOI: 10.1126/science.abf7958

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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.

Science, abf7958, this issue p. 808; see also abi8942, p. 792


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.

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