2. Academic Validation
  3. Structural basis of peptide recognition and activation of endothelin receptors

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

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. duanjia@simm.ac.cn.
  • 4 University of Chinese Academy of Sciences, Beijing, 100049, China. duanjia@simm.ac.cn.
  • 5 Zhongshan Institute for Drug Discovery, Zhongshan, China. duanjia@simm.ac.cn.
  • 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. eric.xu@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, 100049, China. eric.xu@simm.ac.cn.
  • 12 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. eric.xu@simm.ac.cn.
  • 13 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. yjiang@lglab.ac.cn.
  • 14 Lingang Laboratory, Shanghai, 200031, China. yjiang@lglab.ac.cn.
  • # 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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