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

We have investigated the ability of our earlier identified MSO4-MSO5 MSW-pe ptide 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 liga nds. Upon exchanging portions involving transmembrane regions TM1, TM2-3, a nd TM6-7 of the MC1 receptor with corresponding portions of the MC3 recepto r both of these peptides showed major losses of affinities. By contrast exc hanges involving TM4-5 did not appreciably affect the affinity of either MS 04 or MS05. Our data suggest that the binding pocket for the MSO4-MSO5 MSH- peptides is located between TM1-3 and TM6-7 of the melanocortin receptors. (C) 2001 Elsevier Science B.V. All rights reserved.