8IOC

Cryo-EM structure of the gamma-MSH-bound human melanocortin receptor 3 (MC3R)-Gs complex

Summary for 8IOC

• Entry DOI: 10.2210/pdb8ioc/pdb
• EMDB information: 35615
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT, HA signal peptide,Melanocortin receptor 3,LgBiT subunit, ... (7 entities in total)
• Functional Keywords: human melanocortin receptor 3, g protein-coupled receptor, ligand recpgnition, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 165228.84

Authors

Feng, W.B.,Zhou, Q.T.,Chen, X.Y.,Dai, A.T.,Cai, X.Q.,Liu, X.,Zhao, F.H.,Chen, Y.,Ye, C.Y.,Xu, Y.N.,Cong, Z.T.,Li, H.,Lin, S. (deposition date: 2023-03-10, release date: 2023-09-20, Last modification date: 2024-11-06)

Primary citation

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, M.W.
Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.
Cell Discov, 9:81-, 2023

PubMed 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 in complex with γ-MSH and MC5R-G 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 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. PG-901 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.

PubMed: 37524700
DOI: 10.1107/S0907444909042073

Experimental method

ELECTRON MICROSCOPY (2.86 Å)