Structural insights into antagonist recognition by the vasopressin V2 receptor

作者：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, Yi Jiang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64735-x · 被引用次数：6 · 研究领域：Electrolyte and hormonal disorders、Neuroendocrine regulation and behavior、Ion Transport and Channel Regulation

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. The vasopressin V2 receptor (V2R) is a key regulator of water balance, and its antagonists are promising therapeutics for hyponatremia. Here, the authors offer structural insights into antagonist recognition and antagonism of V2R.