Scientists found that a single building block (amino acid 128) in the skin‑color receptor (MC1R) decides whether a tweaked version of the tanning peptide works, and the same spot in a related brain receptor (MC4R) does the same thing. This explains why removing one part of the peptide (Trp9) stops it from affecting appetite‑related receptors but keeps it active for skin‑color signaling.

The melanocortin-1 receptor (MC1R) is a subtype of the melanocortin receptor family and NDP-α-MSH is a non-selective agonist for MC1R. The core sequence of NDP-α-MSH, His-Phe-Arg-Trp, is important for ligand binding and biological activities at the melanocortin receptor subtypes (MCRs). A recent study indicates that Trp⁹ in NDP-α-MSH plays an important role in ligand selectivity. Deletion of Trp⁹ in NDP-α-MSH (des-Trp⁹-NDP-α-MSH) resulted in loss of agonist activity at MC4R, although remains agonist activity at MC1R. The molecular basis for this receptor ligand selectivity is unknown. In this study we examined what region of the MC1R is responsible for des-NDP-α-MSH selectivity. Our results indicate that (1) substitution of TM3 of MC4R with the corresponding region of MC1R switches des-Trp⁹-NDP-α-MSH from no activity to agonist; (2) des-Trp⁹-NDP-α-MSH exhibits agonistic activity at the L133M mutation of the MC4R; and (3) substitution of non-conserved amino acid residue M128 in TM3 of MC1R significantly reduced des-Trp⁹-NDP-α-MSH agonist activity. Our results demonstrate that amino acid residue 128 in TM3 of MC1R, or amino acid residue L133 in TM3 of the MC4R, play crucial roles in ligand des-Trp⁹-NDP-α-MSH selectivity at MC1R or MC4R.