9U81

Cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab

This is a non-PDB format compatible entry.

Summary for 9U81

• Entry DOI: 10.2210/pdb9u81/pdb
• EMDB information: 63949
• Descriptor: anti-BRIL Fab heavy chain, anti-BRIL Fab light chain, Vasopressin V2 receptor,Soluble cytochrome b562, ... (4 entities in total)
• Functional Keywords: gpcr, vasopressin v2 receptor, antagonist, tolvaptan, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 98927.80

Authors

Jiang, Y.,You, C.Z.,Zhang, T.W.,Xu, Y.W.,Tan, Y.X. (deposition date: 2025-03-25, release date: 2025-12-10)

Primary citation

Zhang, T.,Liu, H.,You, C.,Zhang, Y.,Xu, Y.,Pan, B.,Wu, C.,Jin, S.,Yin, Y.L.,Wu, K.,Chen, Y.,Sun, H.,Si, Y.,Tan, Y.,Yin, W.,Xu, H.E.,Guo, D.,Jiang, Y.
Structural insights into antagonist recognition by the vasopressin V2 receptor.
Nat Commun, 16:9734-9734, 2025

PubMed 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.

PubMed: 41188237
DOI: 10.1038/s41467-025-64735-x

Experimental method

ELECTRON MICROSCOPY (3.08 Å)