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1000
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Abstract/Summary
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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 nonselectivity 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–Gs in complex with γ-MSH and MC5R–Gs in the
presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a “Ushape” conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with
MCRs via the HFRW motif. The C-terminus of γ-MSH occupies an MC3R-specific complementary binding groove likely
conferring subtype selectivity, whereas that of α-MSH distances itself from the receptor with neglectable contacts. PG901 achieves the same potency as α-MSH with a shorter length by rebalancing the recognition site and mimicking the
intra-peptide salt bridge in α-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.
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