Journal Article

Structural insights into antagonist recognition by the vasopressin V2 receptor

Wu, Kai, Sun, Hong, Si, Yuan, Tan, Yangxia, Yin, Wanchao, Yin, Yu-Ling, You, Chongzhao, Pan, Benxun, Wu, Canrong, Guo, Dong, Xu, H. Eric, Jiang, Yi, Chen, Yue, Jin, Sanshan, Zhang, Tianwei, Liu, Hongli, Zhang, Yixiao, Xu, Youwei

2025

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 13/95 / 14/28 / 38/70 / 631/45/612/194 / 631/535/1258/1259 / 82/16 / 82/29 / 82/80 / 82/83 / Antagonists / Antidiuretic Hormone Receptor Antagonists - chemistry / Antidiuretic Hormone Receptor Antagonists - metabolism / Antidiuretic Hormone Receptor Antagonists - pharmacology / Binding / Binding Sites / Body water / Cryoelectron Microscopy / Electron microscopy / G protein-coupled receptors / HEK293 Cells / Homeostasis / Humanities and Social Sciences / Humans / Hydrogen bonds / Hyponatremia / Kinases / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Mutation / Protein Binding / Receptors / Receptors, Vasopressin - chemistry / Receptors, Vasopressin - genetics / Receptors, Vasopressin - metabolism / Receptors, Vasopressin - ultrastructure / Recognition / Science / Science (multidisciplinary) / Tolvaptan - chemistry / Tolvaptan - metabolism / Tolvaptan - pharmacology / Vasopressin / Vasopressin V2 receptors / Water balance