Structural insights into the regulation of monomeric and dimeric apelin receptor

Yang Yue, Lier Liu, Lijie Wu, Chanjuan Xu, Man Na, Shenhui Liu, Yuxuan Liu, Fei Li, Junlin Liu, Songting Shi, Hui Lei, Minxuan Zhao, Tianjie Yang, Wei Ji, Arthur Wang, Michael A. Hanson, Raymond C. Stevens, Jianfeng Liu () and Fei Xu ()
Additional contact information
Yang Yue: ShanghaiTech University
Lier Liu: ShanghaiTech University
Lijie Wu: ShanghaiTech University
Chanjuan Xu: Huazhong University of Science and Technology (HUST)
Man Na: ShanghaiTech University
Shenhui Liu: ShanghaiTech University
Yuxuan Liu: Huazhong University of Science and Technology (HUST)
Fei Li: ShanghaiTech University
Junlin Liu: ShanghaiTech University
Songting Shi: Structure Therapeutics
Hui Lei: Structure Therapeutics
Minxuan Zhao: ShanghaiTech University
Tianjie Yang: Chinese Academy of Sciences
Wei Ji: Chinese Academy of Sciences
Arthur Wang: JiKang Therapeutics
Michael A. Hanson: University of Miami
Raymond C. Stevens: Structure Therapeutics
Jianfeng Liu: Huazhong University of Science and Technology (HUST)
Fei Xu: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13. In the dimeric structure, apelin-13 binds exclusively to one protomer that is coupled with Gi proteins, revealing a distinct ligand-binding behavior within APJR homodimers. Furthermore, binding of an antagonistic antibody induces a more compact dimerization by engaging both protomers. Notably, structural analyses of the APJR dimer complexed with an agonistic antibody, with or without Gi proteins, suggest that G protein coupling may promote the dissociation of the APJR dimer during activation. These findings underscore the intricate interplay between ligands, dimerization, and G protein coupling in regulating APJR signaling pathways.

Date: 2025
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DOI: 10.1038/s41467-024-55555-6

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