Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Jiao 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 () and Zhenhua Shao ()
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Jiao Qin: Zhejiang University School of Medicine
Ye Cai: Sichuan University
Zheng Xu: Sichuan University
Qianqian Ming: Zhejiang University Medical Center
Su-Yu Ji: Zhejiang University School of Medicine
Chao Wu: Sichuan University
Huibing Zhang: Zhejiang University School of Medicine
Chunyou Mao: Zhejiang University School of Medicine
Dan-Dan Shen: Zhejiang University School of Medicine
Kunio Hirata: RIKEN SPring-8 Center, Sayo-cho, Sayo-gun
Yanbin Ma: GeneScience Pharmaceutical Co., Ltd.
Wei Yan: Sichuan University
Yan Zhang: Zhejiang University School of Medicine
Zhenhua Shao: Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-27975-9

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