7F83

Crystal Structure of a receptor in Complex with inverse agonist

Summary for 7F83

• Entry DOI: 10.2210/pdb7f83/pdb
• Descriptor: Growth hormone secretagogue receptor type 1,Soluble cytochrome b562, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, 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 (3 entities in total)
• Functional Keywords: gpcr, ghrelin, inverse agonist, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 97531.02

Authors

Xu, Z.,Shao, Z. (deposition date: 2021-07-01, release date: 2022-01-19, Last modification date: 2024-11-13)

Primary citation

Qin, J.,Cai, Y.,Xu, Z.,Ming, Q.,Ji, S.Y.,Wu, C.,Zhang, H.,Mao, C.,Shen, D.D.,Hirata, K.,Ma, Y.,Yan, W.,Zhang, Y.,Shao, Z.
Molecular mechanism of agonism and inverse agonism in ghrelin receptor.
Nat Commun, 13:300-300, 2022

PubMed Abstract: 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.

PubMed: 35027551
DOI: 10.1038/s41467-022-27975-9

Experimental method

X-RAY DIFFRACTION (2.94 Å)