Molecular Mechanism of Agonism and Inverse Agonism in Ghrelin Receptor

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jan 14

PMID 35027551

Authors

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

Zhenhua Shao

Affiliations

Soon will be listed here.

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.

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