Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.

ABSTRACT: Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-G_s in complex with γ-MSH and MC5R-G_s in the presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs

SUBMITTER: Feng W 

PROVIDER: S-EPMC10390531 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature