Structural insights into antagonist recognition by the vasopressin V2 receptor
The vasopressin V2 receptor (V2R), a class A G protein-coupled receptor, is essential for regulating body water homeostasis. V2R antagonists have emerged as promising treatments for hyponatremia; however, the absence of structural information for antagonist-bound V2R hampers our understanding of antagonist recognition and the targeted design of V2R antagonists. In this study, we present two cryo-electron microscopy structures of inactive V2R bound to the clinically approved antagonists tolvaptan and conivaptan. Combined with functional analyses and molecular dynamic simulations, these structures reveal distinct binding poses: tolvaptan is deeply inserted within the binding pocket, whereas conivaptan is positioned at a shallower depth. Integrated analyses further define critical pharmacophoric features governing antagonist activity and unveil a TM7 helical conformation-dependent antagonism mechanism that is distinct from classical GPCR inactivation modes. Our findings deepen understanding of antagonist recognition and antagonism of V2R, providing a foundation for the development of V2R-targeted therapies.
Authors
- Youwei Xu (ORCID: https://orcid.org/0000-0001-8069-7511)
- Canrong Wu (ORCID: https://orcid.org/0000-0002-2272-3838)
- Yangxia Tan (ORCID: https://orcid.org/0000-0003-4419-5180)
- Tianwei Zhang (ORCID: https://orcid.org/0000-0001-6275-3559)
- Benxun Pan (ORCID: https://orcid.org/0000-0001-7982-1706)
- H. Eric Xu (ORCID: https://orcid.org/0000-0002-6829-8144)
- Chongzhao You (ORCID: https://orcid.org/0000-0002-6425-3387)
- Yue Chen (ORCID: https://orcid.org/0000-0001-6784-3334)
- Yi Jiang (ORCID: https://orcid.org/0000-0002-0723-1413)
- Kai Wu (ORCID: https://orcid.org/0000-0002-7913-8322)
- Wanchao Yin (ORCID: https://orcid.org/0000-0002-6889-4907)
- Hongli Liu (ORCID: https://orcid.org/0000-0003-0670-0289)
- Yixiao Zhang (ORCID: https://orcid.org/0000-0003-1540-4334)
- Yuan Si (ORCID: https://orcid.org/0009-0009-0608-7868)
- Sanshan Jin (ORCID: https://orcid.org/0000-0002-2523-1767)
- Dong Guo (ORCID: https://orcid.org/0000-0001-6142-4825)
- Yu-Ling Yin
- Hong Sun
Institutions
- Xuzhou Medical College (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Ruijin Hospital (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s41467-025-64735-x
- Citations
- 2
- Primary Topic
- Electrolyte and hormonal disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- China Postdoctoral Science Foundation
- National Key Research and Development Program of China
- Program of Shanghai Academic Research Leader