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TitleMolecular recognition of an acyl-peptide hormone and activation of ghrelin receptor.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 5064, Year 2021
Publish dateAug 20, 2021
AuthorsYue Wang / Shimeng Guo / Youwen Zhuang / Ying Yun / Peiyu Xu / Xinheng He / Jia Guo / Wanchao Yin / H Eric Xu / Xin Xie / Yi Jiang /
PubMed AbstractGhrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature ...Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of G-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.
External linksNat Commun / PubMed:34417468 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.2 Å
Structure data

31500

7f9y

EMDB-31500, PDB-7f9y:
ghrelin-bound ghrelin receptor in complex with Gq
Method: EM (single particle) / Resolution: 2.9 Å

31501

7f9z

EMDB-31501, PDB-7f9z:
GHRP-6-bound ghrelin receptor in complex with Gq
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-OCA:
OCTANOIC ACID (CAPRYLIC ACID) / Caprylic acid

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / ghrelin / GPCR / Gq / GHRP-6

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