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TitleMechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7403, Year 2025
Publish dateAug 11, 2025
AuthorsYang 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 AbstractThe 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 linksNat Commun / PubMed:40790299 / PubMed Central
MethodsEM (single particle)
Resolution3.21 - 3.57 Å
Structure data

EMDB-62581, PDB-9kuv:
Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-62582, PDB-9kuw:
Cryo-EM structure of dimeric APJR and two Beta-arrestins complex with small molecules
Method: EM (single particle) / Resolution: 3.49 Å

EMDB-62583, PDB-9kux:
Cryo-EM structure of dimeric APJR and one Beta-arrestin complex with small molecules
Method: EM (single particle) / Resolution: 3.57 Å

Chemicals

PDB-1l6r:
Crystal Structure of Thermoplasma acidophilum 0175 (APC0014)

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / APJR / Beta-arrestin / GPCR

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