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Abstract
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-G
s 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 Ca
2+ 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.View Full Text ....

Israel General , Hebrew University , Cancer Research , Institute For Medical Research Israel , Hadassah Medical School , Department Of Developmental Biology , Developmental Biology , Medical Research Israel Canada , இஸ்ரேல் ஜநரல் , ஹீப்ரு பல்கலைக்கழகம் , புற்றுநோய் ஆராய்ச்சி , ஹடாஸா மருத்துவ பள்ளி , துறை ஆஃப் வளர்ச்சி உயிரியல் , வளர்ச்சி உயிரியல் , மருத்துவ ஆராய்ச்சி இஸ்ரேல் கனடா ,