Structural insights into antagonist recognition by the vasopressin V2 receptor

Tianwei Zhang, Hongli Liu, Chongzhao You, Yixiao Zhang, Youwei Xu, Benxun Pan, Canrong Wu, Sanshan Jin, Yu-Ling Yin, Kai Wu, Yue Chen, Hong Sun, Yuan Si, Yangxia Tan, Wanchao Yin, H. Eric Xu (), Dong Guo () and Yi Jiang ()
Additional contact information
Tianwei Zhang: Lingang Laboratory
Hongli Liu: Xuzhou Medical University
Chongzhao You: Chinese Academy of Sciences
Yixiao Zhang: Xuzhou Medical University
Youwei Xu: Chinese Academy of Sciences
Benxun Pan: Lingang Laboratory
Canrong Wu: Shanghai Jiao Tong University School of Medicine
Sanshan Jin: Lingang Laboratory
Yu-Ling Yin: Lingang Laboratory
Kai Wu: Chinese Academy of Sciences
Yue Chen: Xuzhou Medical University
Hong Sun: Xuzhou Medical University
Yuan Si: Lingang Laboratory
Yangxia Tan: Lingang Laboratory
Wanchao Yin: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Dong Guo: Xuzhou Medical University
Yi Jiang: Lingang Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64735-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64735-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-64735-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().