Structural basis of peptide recognition and activation of endothelin receptors

  • Nat Commun. 2023 Mar 7;14(1):1268. doi: 10.1038/s41467-023-36998-9.
Yujie Ji  #  1  2 ,  Jia Duan  #  3  4  5 ,  Qingning Yuan  #  1 ,  Xinheng He  1  2 ,  Gong Yang  6 ,  Shengnan Zhu  7 ,  Kai Wu  1 ,  Wen Hu  1 ,  Tianyu Gao  8 ,  Xi Cheng  1  2 ,  Hualiang Jiang  1  2  8  9 ,  H Eric Xu  10  11  12 ,  Yi Jiang  13  14
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 4. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 5. Zhongshan Institute for Drug Discovery, Zhongshan, China. [email protected].
  • 6. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, 361005, China.
  • 7. School of Pharmacy, Macau University of Science and Technology, Macau, 999078, China.
  • 8. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 9. Lingang Laboratory, Shanghai, 200031, China.
  • 10. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 12. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 13. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 14. Lingang Laboratory, Shanghai, 200031, China. [email protected].
  • # Contributed equally.
PMID: 36882417 DOI: 10.1038/s41467-023-36998-9
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.

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