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Structural basis of peptide recognition and activation of endothelin receptors

Author

Listed:
  • Yujie Ji

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

  • Jia Duan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Zhongshan Institute for Drug Discovery)

  • Qingning Yuan

    (Chinese Academy of Sciences)

  • Xinheng He

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

  • Gong Yang

    (Xiamen University)

  • Shengnan Zhu

    (Macau University of Science and Technology)

  • Kai Wu

    (Chinese Academy of Sciences)

  • Wen Hu

    (Chinese Academy of Sciences)

  • Tianyu Gao

    (ShanghaiTech University)

  • Xi Cheng

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

  • Hualiang Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University
    Lingang Laboratory)

  • H. Eric Xu

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

  • Yi Jiang

    (ShanghaiTech University
    Lingang Laboratory)

Abstract

Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes—endothelin receptor A (ETAR) and B (ETBR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETAR and ETBR bound to ET-1 and ETBR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.

Suggested Citation

  • Yujie Ji & Jia Duan & Qingning Yuan & Xinheng He & Gong Yang & Shengnan Zhu & Kai Wu & Wen Hu & Tianyu Gao & Xi Cheng & Hualiang Jiang & H. Eric Xu & Yi Jiang, 2023. "Structural basis of peptide recognition and activation of endothelin receptors," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36998-9
    DOI: 10.1038/s41467-023-36998-9
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    References listed on IDEAS

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