9KUV

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

This is a non-PDB format compatible entry.

Summary for 9KUV

• Entry DOI: 10.2210/pdb9kuv/pdb
• EMDB information: 62581
• Descriptor: Beta-arrestin-scFv30, Apelin Receptor, (1~{S},2~{S})-~{N}-[4-(2,6-dimethoxyphenyl)-5-(6-methylpyridin-2-yl)-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-oxidanyl-propane-2-sulfonamide, ... (4 entities in total)
• Functional Keywords: apjr, beta-arrestin, gpcr, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 126866.66

Authors

Yue, Y.,Wu, L.J.,Xu, F. (deposition date: 2024-12-04, release date: 2025-09-17)

Primary citation

Yue, Y.,Xu, C.,Wu, L.,Na, M.,Xu, K.,Chen, X.,Song, Y.,Weng, S.,Xu, L.,Li, F.,Lin, X.,Wang, A.,Liu, J.,Xu, F.
Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex.
Nat Commun, 16:7403-7403, 2025

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 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.

PubMed: 40790299
DOI: 10.1038/s41467-025-62870-z

Experimental method

ELECTRON MICROSCOPY (3.21 Å)