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Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor

Author

Listed:
  • Yue Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shimeng Guo

    (Nanjing University of Chinese Medicine
    Chinese Academy of Sciences)

  • Youwen Zhuang

    (Chinese Academy of Sciences)

  • Ying Yun

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Peiyu Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jia Guo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wanchao Yin

    (Chinese Academy of Sciences)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Nanjing University of Chinese Medicine
    ShanghaiTech University)

  • Xin Xie

    (University of Chinese Academy of Sciences
    Nanjing University of Chinese Medicine
    Chinese Academy of Sciences
    ShanghaiTech University)

  • Yi Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.

Suggested Citation

  • Yue Wang & Shimeng Guo & Youwen Zhuang & Ying Yun & Peiyu Xu & Xinheng He & Jia Guo & Wanchao Yin & H. Eric Xu & Xin Xie & Yi Jiang, 2021. "Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25364-2
    DOI: 10.1038/s41467-021-25364-2
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    Cited by:

    1. Dohyun Im & Jun-ichi Kishikawa & Yuki Shiimura & Hiromi Hisano & Akane Ito & Yoko Fujita-Fujiharu & Yukihiko Sugita & Takeshi Noda & Takayuki Kato & Hidetsugu Asada & So Iwata, 2023. "Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Xinyan Zhu & Yu Qian & Xiaowan Li & Zhenmei Xu & Ruixue Xia & Na Wang & Jiale Liang & Han Yin & Anqi Zhang & Changyou Guo & Guangfu Wang & Yuanzheng He, 2022. "Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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