Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. α-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Mer 4-Glu-His-Phe 7-Arg-Trp-Gly-Lys-Pro-Val-NH 2 (α-MSH, α-melanotropin). and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle 4-Glu-His-DPhe 7-Arg-Trp-Gly-Lys-Pro-Val-NH 2 (NDP-MSH) and Ac-Nle 4-c[Asp 5-His 6-DPhe 7-Arg 8-Trp 9-Lys 1u]-NH 2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe 7 and Trp 9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg 8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on α-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing α-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.
|Original language||English (US)|
|Number of pages||15|
|Journal||Drug Design and Discovery|
|State||Published - 1996|
- GPCR model
- α-melanocyte stimulating hormone