Structural basis of peptide recognition and activation of endothelin receptors

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 () and Yi Jiang ()
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Yujie Ji: Chinese Academy of Sciences
Jia Duan: Chinese Academy of Sciences
Qingning Yuan: Chinese Academy of Sciences
Xinheng He: 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
Hualiang Jiang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Yi Jiang: ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36998-9

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