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- EMDB-51986: Local refinement TVP-V2R (Cryo-EM structure of inactive human arg... -

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Basic information

Entry
Database: EMDB / ID: EMD-51986
TitleLocal refinement TVP-V2R (Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan)
Map data
Sample
  • Complex: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL Fab and anti-BRIL Fab Nanobody
KeywordsGPCR / V2R / TVP / tolvaptan / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsBous J / Fouillen A / Couvineau P / Orcel H / Mary C / Mendre C / Schulte G / Granier S / Gilles N / Mouillac B
Funding support France, European Union, 3 items
OrganizationGrant numberCountry
Agence Nationale de la Recherche (ANR)ANR-19-CE11-0014 France
Agence Nationale de la Recherche (ANR)ANR-22-CE44-0021 France
H2020 Marie Curie Actions of the European Commission101063049_3D-V2REuropean Union
CitationJournal: Nat Commun / Year: 2025
Title: Inactive structures of the vasopressin V2 receptor reveal distinct binding modes for Tolvaptan and Mambaquaretin toxin.
Authors: Aurélien Fouillen / Julien Bous / Pierre Couvineau / Hélène Orcel / Charline Mary / Lucie Lafleur / Timothé Pierre / Christiane Mendre / Nicolas Gilles / Gunnar Schulte / Sébastien ...Authors: Aurélien Fouillen / Julien Bous / Pierre Couvineau / Hélène Orcel / Charline Mary / Lucie Lafleur / Timothé Pierre / Christiane Mendre / Nicolas Gilles / Gunnar Schulte / Sébastien Granier / Bernard Mouillac /
Abstract: Inhibitors of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds for treating hyponatremia or polycystic kidney diseases. Rational drug design based on experimental G ...Inhibitors of the arginine-vasopressin (AVP) V2 receptor (V2R) are key therapeutic compounds for treating hyponatremia or polycystic kidney diseases. Rational drug design based on experimental G protein-coupled receptor structures is a powerful avenue to develop better drugs. So far, the lack of inhibitor-bound V2R structures has impaired this strategy. Here we describe the cryo-electron microscopy structures of the V2R in complex with two selective inverse agonists, the non-peptide Tolvaptan (TVP) and the green mamba snake Mambaquaretin toxin (MQ1). Both ligands bind into the orthosteric binding site but with substantial differences. TVP binds deeper than MQ1, and directly contacts the toggle switch residue W284 in the transmembrane domain 6. The Kunitz-fold toxin displays extensive contacts with extracellular and transmembrane residues. As anticipated from TVP and MQ1 pharmacological properties, both structures represent inactive V2R conformations. Their comparison with those of the active AVP-bound V2R reveals the molecular mechanisms modulating receptor activity. The mini-protein MQ1-bound V2R structure suggests a new pharmacology approach for treating water homeostasis and renal diseases.
History
DepositionNov 4, 2024-
Header (metadata) releaseSep 10, 2025-
Map releaseSep 10, 2025-
UpdateSep 10, 2025-
Current statusSep 10, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51986.png

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Map

FileDownload / File: emd_51986.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.02 Å/pix.
x 300 pix.
= 304.56 Å		1.02 Å/pix.
x 300 pix.
= 304.56 Å		1.02 Å/pix.
x 300 pix.
= 304.56 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0152 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0526
Minimum - Maximum-0.44991416 - 2.16354
Average (Standard dev.)-0.00019530594 (±0.0069386014)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 304.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51986_msk_1.map
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Additional map: #1

Fileemd_51986_additional_1.map
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Half map: #1

Fileemd_51986_half_map_1.map
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Half map: #2

Fileemd_51986_half_map_2.map
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Sample components

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Entire : Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL F...

EntireName: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL Fab and anti-BRIL Fab Nanobody
Components
  • Complex: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL Fab and anti-BRIL Fab Nanobody

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Supramolecule #1: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL F...

SupramoleculeName: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL Fab and anti-BRIL Fab Nanobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 115 KDa

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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

Concentration22 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R0.6/1 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.5.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5.1) / Number images used: 161260
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.1)
Final 3D classificationSoftware - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT

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