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Publication Abstract from PubMed

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.

Structural insights into antagonist recognition by the vasopressin V2 receptor.,Zhang T, Liu H, You C, Zhang Y, Xu Y, Pan B, Wu C, Jin S, Yin YL, Wu K, Chen Y, Sun H, Si Y, Tan Y, Yin W, Xu HE, Guo D, Jiang Y Nat Commun. 2025 Nov 4;16(1):9734. doi: 10.1038/s41467-025-64735-x. PMID:41188237^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.