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Publication Abstract from PubMed

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 gamma-MSH and non-selectivity of agonist alpha-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 gamma-MSH and MC5R-G(s) in the presence of alpha-MSH or a potent synthetic agonist PG-901. The structures reveal that alpha-MSH and gamma-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of gamma-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of alpha-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as alpha-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in alpha-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members.

Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.,Feng W, Zhou Q, Chen X, Dai A, Cai X, Liu X, Zhao F, Chen Y, Ye C, Xu Y, Cong Z, Li H, Lin S, Yang D, Wang MW Cell Discov. 2023 Jul 31;9(1):81. doi: 10.1038/s41421-023-00586-4. PMID:37524700^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.