2. Academic Validation
  3. Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex

Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex

  • Nat Commun. 2025 Aug 11;16(1):7403. doi: 10.1038/s41467-025-62870-z.
Yang Yue # 1,  Chanjuan Xu # 2,  Lijie Wu # 1,  Man Na 1 3,  Kexin Xu 1 3,  Xuan Chen 2,  Yuxuan Song 2,  Sichun Weng 2,  Lu Xu 1 4,  Fei Li 1,  Xi Lin 1,  Arthur Wang 4,  Jianfeng Liu 5,  Fei Xu 6 7 8 9
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 2 Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 4 JiKang Therapeutics, Shanghai, China.
  • 5 Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China. jfliu@mail.hust.edu.cn.
  • 6 iHuman Institute, ShanghaiTech University, Shanghai, China. xufei@shanghaitech.edu.cn.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. xufei@shanghaitech.edu.cn.
  • 8 JiKang Therapeutics, Shanghai, China. xufei@shanghaitech.edu.cn.
  • 9 Shanghai Clinical Research and Trial Center, Shanghai, China. xufei@shanghaitech.edu.cn.
  • # Contributed equally.
PMID: 40790299 DOI: 10.1038/s41467-025-62870-z
Abstract

The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health1,2. Understanding the mechanisms of biased agonism at APJR is crucial for drug discovery, as stimulation of the β-arrestin pathway may lead to some adverse effects3. Structural analyses of APJR-Gi complexes have clarified the structural basis of receptor dimerization and activation4,5, yet the absence of structural data on APJR-arrestin complexes has impeded a comprehensive understanding of APJR stoichiometry in the dual signaling pathways and biased agonism. Here, we present APJR-β-arrestin1 structures bound to a clinical drug analog, revealing 2:2 and 2:1 stoichiometries associated with differential β-arrestin recruitment. Through comparison of the two transducer-coupled APJR structures bound to the same ligand, we identify key residues and motifs crucial for directing biased signaling. These findings highlight APJR's versatile stoichiometry in coupling with β-arrestin and Gi proteins, establishing a framework for understanding biased agonism and guiding the development of therapeutics.

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