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TitleStructural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor.
Journal, issue, pagesCell Res, Vol. 31, Issue 10, Page 1061-1071, Year 2021
Publish dateAug 27, 2021
AuthorsShanshan Ma / Yan Chen / Antao Dai / Wanchao Yin / Jia Guo / Dehua Yang / Fulai Zhou / Yi Jiang / Ming-Wei Wang / H Eric Xu /
PubMed AbstractMelanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled ...Melanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R-MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gβ subunit were discovered from these structures. Together, our results elucidate a conserved mechanism of calcium-mediated ligand recognition, a specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.
External linksCell Res / PubMed:34453129 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.1 Å
Structure data

EMDB-31448, PDB-7f4d:
Cryo-EM structure of alpha-MSH-bound melanocortin-1 receptor in complex with Gs protein and Nb35
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-31449, PDB-7f4f:
Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-31452, PDB-7f4h:
Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein, Nb35 and scFv16
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-31453, PDB-7f4i:
Cryo-EM structure of SHU9119-bound melanocortin-1 receptor in complex with Gs protein and Nb35
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptors / melanocyte / clacium ion / activation / MC1R

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