Good news! Obesity be gone!
"... MC4 is a prime target for anti-obesity drugs, such as setmelanotide, precisely because it's a master switch: turning it on can control hunger while bypassing all other energy-related signals. But until now it was unknown how exactly this hunger switch works. ...
The new study began with the predicament of one family, in which at least eight members, plagued by persistent hunger, were severely obese – most of them with a body mass index of over 70, that is, about triple the norm. Their medical history came to the attention of [researchers] struck by the fact that the family's plight was due to a single mutation that ran in the family: one affecting the MC4 receptor. ....
The 3D structure revealed that setmelanotide activates the MC4 receptor by entering its binding pocket – that is, by directly hitting the molecular switch that signals satiety, even more potently than the natural satiety hormone. It also turned out that the drug has a surprising helper: an ion of calcium that enters the pocket, enhancing the drug's binding to the receptor. In biochemical and computational experiments, the scientists found that similarly to the drug, calcium also assists the natural satiety hormone. ..."
The new study began with the predicament of one family, in which at least eight members, plagued by persistent hunger, were severely obese – most of them with a body mass index of over 70, that is, about triple the norm. Their medical history came to the attention of [researchers] struck by the fact that the family's plight was due to a single mutation that ran in the family: one affecting the MC4 receptor. ....
The 3D structure revealed that setmelanotide activates the MC4 receptor by entering its binding pocket – that is, by directly hitting the molecular switch that signals satiety, even more potently than the natural satiety hormone. It also turned out that the drug has a surprising helper: an ion of calcium that enters the pocket, enhancing the drug's binding to the receptor. In biochemical and computational experiments, the scientists found that similarly to the drug, calcium also assists the natural satiety hormone. ..."
"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."
Here is the link to the underlying research article:
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