Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex
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...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62870-z |
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| Summary: | 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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| ISSN: | 2041-1723 |