Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling
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Obesity is a global epidemic causing 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-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 Ca2+ is required for agonist but not antagonist efficacy. These results fill a gap in understanding MC4R activation and could guide the design of future weight management drugs.
AuthorsIsraeli, H; Degtjarik, O; Fierro, F; Chunilal, V; Gill, AK; Roth, NJ; Botta, J; Prabahar, V; Peleg, Y; Chan, LF
- Centre for Endocrinology