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TitleStructural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 6410, Year 2021
Publish dateNov 4, 2021
AuthorsHeng Liu / Dapeng Sun / Alexander Myasnikov / Marjorie Damian / Jean-Louis Baneres / Ji Sun / Cheng Zhang /
PubMed AbstractThe hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its ...The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-G signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the G and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.
External linksNat Commun / PubMed:34737341 / PubMed Central
MethodsEM (single particle)
Resolution2.7 Å
Structure data

24267

7na7

EMDB-24267, PDB-7na7:
Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist
Method: EM (single particle) / Resolution: 2.7 Å

24268

7na8

EMDB-24268, PDB-7na8:
Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-1KD:
1-(methanesulfonyl)-1'-(2-methyl-L-alanyl-O-benzyl-D-seryl)-1,2-dihydrospiro[indole-3,4'-piperidine] / agonist, hormone*YM

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / appetite / energy homeostasis / reward signaling

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