Detection of regions in the MC₁ receptor of importance for the selectivity of the MC₁ receptor super-selective MS04/MS05 peptides

We have investigated the ability of our earlier identified MS04-MS05 MSH-peptide analogues to bind to chimeric MC₁-MC₃ receptors. While the MS04 and MS05 peptides bind with nanomolar and sub-nanomolar affinities to the wild type MC₁ receptor, they bind only with micromolar affinities for the wild type MC₃ receptor, thus being the hitherto most MC₁ receptor selective ligands. Upon exchanging portions involving transmembrane regions TM1, TM2-3, and TM6-7 of the MC₁ receptor with corresponding portions of the MC₃ receptor both of these peptides showed major losses of affinities. By contrast exchanges involving TM4-5 did not appreciably affect the affinity of either MS04 or MS05. Our data suggest that the binding pocket for the MS04-MS05 MSH-peptides is located between TM1-3 and TM6-7 of the melanocortin receptors.