2. Academic Validation
  3. Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

  • Nat Commun. 2022 Jan 13;13(1):300. doi: 10.1038/s41467-022-27975-9.
Jiao Qin # 1 2 3 4 5,  Ye Cai # 2,  Zheng Xu # 2,  Qianqian Ming # 3,  Su-Yu Ji # 1 3 4 5,  Chao Wu # 2,  Huibing Zhang 1 3 4 5,  Chunyou Mao 6,  Dan-Dan Shen 1 3 4 5,  Kunio Hirata 7,  Yanbin Ma 8,  Wei Yan 9,  Yan Zhang 10 11 12 13,  Zhenhua Shao 14
Affiliations

Affiliations

  • 1 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
  • 2 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
  • 3 Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, China.
  • 4 MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang, China.
  • 5 Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, 310058, Hangzhou, China.
  • 6 Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.
  • 7 RIKEN SPring-8 Center, Sayo-cho, Sayo-gun, Hyogo, 679-5165, Japan.
  • 8 Institute of innovation, GeneScience Pharmaceutical Co., Ltd., Shanghai, China. [email protected].
  • 9 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. [email protected].
  • 10 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. [email protected].
  • 11 Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, China. [email protected].
  • 12 MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang, China. [email protected].
  • 13 Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, 310058, Hangzhou, China. [email protected].
  • 14 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China. [email protected].
  • # Contributed equally.
PMID: 35027551 DOI: 10.1038/s41467-022-27975-9
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.

Figures