7W2Z

Cryo-EM structure of the ghrelin-bound human ghrelin receptor-Go complex

Summary for 7W2Z

• Entry DOI: 10.2210/pdb7w2z/pdb
• EMDB information: 32268
• Descriptor: Guanine nucleotide-binding protein G(o) subunit alpha, Growth hormone secretagogue receptor type 1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, ghrelin, endogenous agonist, class a gpcr, peptide receptor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 142349.50

Authors

Qin, J.,Ming, Q.,Ji, S.,Mao, C.,Shen, D.,Zhang, Y. (deposition date: 2021-11-24, release date: 2022-01-19, Last modification date: 2022-02-16)

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

ELECTRON MICROSCOPY (2.8 Å)