2. Academic Validation
  3. Structural insights into antagonist recognition by the vasopressin V2 receptor

Structural insights into antagonist recognition by the vasopressin V2 receptor

  • Nat Commun. 2025 Nov 4;16(1):9734. doi: 10.1038/s41467-025-64735-x.
Tianwei Zhang # 1 2,  Hongli Liu # 3,  Chongzhao You # 4,  Yixiao Zhang 3,  Youwei Xu 4,  Benxun Pan 1,  Canrong Wu 5,  Sanshan Jin 1 2,  Yu-Ling Yin 1,  Kai Wu 6,  Yue Chen 3,  Hong Sun 3,  Yuan Si 1,  Yangxia Tan 1,  Wanchao Yin 7,  H Eric Xu 8 9 10,  Dong Guo 11,  Yi Jiang 12 13
Affiliations

Affiliations

  • 1 Lingang Laboratory, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 9 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10 The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 12 Lingang Laboratory, Shanghai, China. [email protected].
  • 13 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41188237 DOI: 10.1038/s41467-025-64735-x
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.

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