The melanocortin system is essential for survival, with the melanocortin-3 and -4 receptors (hMC3R and hMC4R) regulating energy homeostasis and metabolism, and the melanocortin-1 receptor (hMC1R) controlling pigmentation and skin cancer prevention. However, achieving subtype selectivity among these receptors remains challenging due to their high sequence similarity. Here, we first systematically examined the impact of the α-MSH C-terminal tripeptide –Lys-Pro-Val (–KPV) on melanotropin conformation and receptor selectivity.
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