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TitleMolecular mechanism of agonism and inverse agonism in ghrelin receptor.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 300, Year 2022
Publish dateJan 13, 2022
AuthorsJiao Qin / Ye Cai / Zheng Xu / Qianqian Ming / Su-Yu Ji / Chao Wu / Huibing Zhang / Chunyou Mao / Dan-Dan Shen / Kunio Hirata / Yanbin Ma / Wei Yan / Yan Zhang / Zhenhua Shao /
PubMed AbstractMuch effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are ...Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.
External linksNat Commun / PubMed:35027551 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.8 - 2.94 Å
Structure data

32268

7w2z

EMDB-32268, PDB-7w2z:
Cryo-EM structure of the ghrelin-bound human ghrelin receptor-Go complex
Method: EM (single particle) / Resolution: 2.8 Å

PDB-7f83:
Crystal Structure of a receptor in Complex with inverse agonist
Method: X-RAY DIFFRACTION / Resolution: 2.94 Å

Chemicals

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-1KQ:
2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN / GPCR / Ghrelin / Inverse agonist / endogenous agonist / Class A GPCR / Peptide receptor

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