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| Title | Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 7403, Year 2025 |
| Publish date | Aug 11, 2025 |
Authors | Yang Yue / Chanjuan Xu / Lijie Wu / Man Na / Kexin Xu / Xuan Chen / Yuxuan Song / Sichun Weng / Lu Xu / Fei Li / Xi Lin / Arthur Wang / Jianfeng Liu / Fei Xu / ![]() |
| PubMed Abstract | The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health. Understanding the mechanisms of biased agonism at APJR is crucial for drug discovery, as stimulation ...The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health. 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 effects. Structural analyses of APJR-Gi complexes have clarified the structural basis of receptor dimerization and activation, 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. |
External links | Nat Commun / PubMed:40790299 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.21 - 3.57 Å |
| Structure data | EMDB-62581, PDB-9kuv: EMDB-62582, PDB-9kuw: EMDB-62583, PDB-9kux: |
| Chemicals | ![]() PDB-1l6r: ![]() ChemComp-CLR: |
| Source |
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Keywords | SIGNALING PROTEIN / APJR / Beta-arrestin / GPCR |
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homo sapiens (human)
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