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- EMDB-63949: Cryo-EM structure of tolvaptan-bound human vasopressin V2 recepto... -

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Basic information

Entry
Database: EMDB / ID: EMD-63949
TitleCryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
Map data
Sample
  • Complex: cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
    • Protein or peptide: anti-BRIL Fab heavy chain
    • Protein or peptide: anti-BRIL Fab light chain
    • Protein or peptide: Vasopressin V2 receptor,Soluble cytochrome b562
  • Ligand: Tolvaptan
KeywordsGPCR / vasopressin V2 receptor / antagonist / tolvaptan / MEMBRANE PROTEIN/IMMUNE SYSTEM / 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
Soluble cytochrome b562 / Vasopressin V2 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsJiang Y / You CZ / Zhang TW / Xu YW / Tan YX
Funding support China, 1 items
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, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63949.png

Downloads & links

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Map

FileDownload / File: emd_63949.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.36
Minimum - Maximum-2.2010274 - 3.1883316
Average (Standard dev.)-0.0020625666 (±0.049092826)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_63949_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_63949_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : cryo-EM structure of tolvaptan-bound human vasopressin V2 recepto...

EntireName: cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
Components
  • Complex: cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
    • Protein or peptide: anti-BRIL Fab heavy chain
    • Protein or peptide: anti-BRIL Fab light chain
    • Protein or peptide: Vasopressin V2 receptor,Soluble cytochrome b562
  • Ligand: Tolvaptan

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Supramolecule #1: cryo-EM structure of tolvaptan-bound human vasopressin V2 recepto...

SupramoleculeName: cryo-EM structure of tolvaptan-bound human vasopressin V2 receptor complex with Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: anti-BRIL Fab heavy chain

MacromoleculeName: anti-BRIL Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.321084 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: ELSEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
ELSEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK S

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Macromolecule #2: anti-BRIL Fab light chain

MacromoleculeName: anti-BRIL Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.586205 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVEIK RTVAAPSVFI FPPSDSQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC

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Macromolecule #3: Vasopressin V2 receptor,Soluble cytochrome b562

MacromoleculeName: Vasopressin V2 receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.571574 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MLMASTTSAV PGHPSLPSLP SNSSQERPLD TRDPLLARAE LALLSIVFVA VALSNGLVLA ALARRGRRGH WAPIHVFIGH LCLADLAVA LFQVLPQLAW KATDRFRGPD ALCRAVKYLQ MVGMYASSYM ILAMTLDRHR AICRPMLAYR HGSGAHWNRP V LVAWAFSL ...String:
MLMASTTSAV PGHPSLPSLP SNSSQERPLD TRDPLLARAE LALLSIVFVA VALSNGLVLA ALARRGRRGH WAPIHVFIGH LCLADLAVA LFQVLPQLAW KATDRFRGPD ALCRAVKYLQ MVGMYASSYM ILAMTLDRHR AICRPMLAYR HGSGAHWNRP V LVAWAFSL LLSLPQLFIF AQRNVEGGSG VTDCWACFAE PWGRRTYVTW IALMVFVAPT LGIAACQVLI FREIHAARRQ LA DLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPKL EDKSPDSPEM KDFRHGFDIL VGQIDDALKL ANE GKVKEA QAAAEQLKTT RNAYIQKYLE RARSTLAAVA KTVRMTLVIV VVYVLCWAPF FLVQLWAAWD PEAPLEGAPF VLLM LLASL NSCTNPWIYA SFSSSVSSEL RSLLCCARGR TPPSLGPQDE SCTTASSSLA KDTSS

UniProtKB: Vasopressin V2 receptor, Soluble cytochrome b562, Vasopressin V2 receptor

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Macromolecule #4: Tolvaptan

MacromoleculeName: Tolvaptan / type: ligand / ID: 4 / Number of copies: 1 / Formula: A1ECF
Molecular weightTheoretical: 448.941 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 30.0 µm / Nominal defocus min: 5.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 326036
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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