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- PDB-9u81: Cryo-EM structure of tolvaptan-bound human vasopressin V2 recepto... -

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Basic information

Entry
Database: PDB / ID: 9u81
TitleCryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
Components
  • Vasopressin V2 receptor,Soluble cytochrome b562
  • anti-BRIL Fab heavy chain
  • anti-BRIL Fab light chain
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / vasopressin V2 receptor / antagonist / tolvaptan / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / hemostasis / telencephalon development / positive regulation of vasoconstriction / positive regulation of systemic arterial blood pressure / positive regulation of intracellular signal transduction ...renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / hemostasis / telencephalon development / positive regulation of vasoconstriction / positive regulation of systemic arterial blood pressure / positive regulation of intracellular signal transduction / endocytic vesicle / activation of adenylate cyclase activity / cellular response to hormone stimulus / response to cytokine / clathrin-coated endocytic vesicle membrane / electron transport chain / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / G alpha (s) signalling events / electron transfer activity / periplasmic space / endosome / iron ion binding / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / positive regulation of cell population proliferation / heme binding / positive regulation of gene expression / perinuclear region of cytoplasm / endoplasmic reticulum / Golgi apparatus / membrane / plasma membrane
Similarity search - Function
Vasopressin V2 receptor / Vasopressin receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
: / Soluble cytochrome b562 / Vasopressin V2 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsJiang, Y. / You, C.Z. / Zhang, T.W. / Xu, Y.W. / Tan, Y.X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into antagonist recognition by the vasopressin V2 receptor.
Authors: 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 ...Authors: 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 /
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; ...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.
History
DepositionMar 25, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 10, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: anti-BRIL Fab heavy chain
L: anti-BRIL Fab light chain
R: Vasopressin V2 receptor,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9284
Polymers98,4793
Non-polymers4491
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody anti-BRIL Fab heavy chain


Mass: 24321.084 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#2: Antibody anti-BRIL Fab light chain


Mass: 23586.205 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#3: Protein Vasopressin V2 receptor,Soluble cytochrome b562 / V2R / AVPR V2 / Antidiuretic hormone receptor / Renal-type arginine vasopressin receptor / Cytochrome b-562


Mass: 50571.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: AVPR2, ADHR, DIR, DIR3, V2R, cybC / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P30518, UniProt: P0ABE7
#4: Chemical ChemComp-A1ECF / Tolvaptan / N-[4-[[(5S)-7-chloranyl-5-oxidanyl-2,3,4,5-tetrahydro-1-benzazepin-1-yl]carbonyl]-3-methyl-phenyl]-2-methyl-benzamide


Mass: 448.941 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25ClN2O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 30000 nm / Nominal defocus min: 5000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 326036 / Symmetry type: POINT
RefinementHighest resolution: 3.08 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036428
ELECTRON MICROSCOPYf_angle_d0.5298758
ELECTRON MICROSCOPYf_dihedral_angle_d6.424893
ELECTRON MICROSCOPYf_chiral_restr0.043997
ELECTRON MICROSCOPYf_plane_restr0.0041102

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