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- EMDB-51988: Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2... -

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Basic information

Entry
Database: EMDB / ID: EMD-51988
TitleCryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan
Map dataComposite map of V2R inactive bound to TVP
Sample
  • Complex: Inactive V2R-bril bound to tolvaptan stabillized with anti-BRIL Fab and anti-BRIL Fab Nanobody
    • Protein or peptide: Synthetic antibody, anti-BRIL Fab fragment, Heavy chain
    • Protein or peptide: anti-BRIL Fab Nanobody
    • Protein or peptide: Synthetic antibody, anti-BRIL Fab fragment, Light chain
    • Protein or peptide: Vasopressin V2 receptor,Soluble cytochrome b562
  • Ligand: (R)-Tolvaptan
KeywordsGPCR / V2R / TVP / tolvaptan / MEMBRANE PROTEIN
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 systemic arterial blood pressure / positive regulation of intracellular signal transduction / endocytic vesicle ...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 systemic arterial blood pressure / positive regulation of intracellular signal transduction / endocytic vesicle / cellular response to hormone stimulus / activation of adenylate cyclase activity / positive regulation of vasoconstriction / 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 / periplasmic space / electron transfer activity / endosome / G protein-coupled receptor signaling pathway / iron ion binding / 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)
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) releaseJun 4, 2025-
Map releaseJun 4, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51988.png

Downloads & links

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Map

FileDownload / File: emd_51988.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map of V2R inactive bound to TVP
Projections & slices

Image control

Size
Brightness
Contrast
Others
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

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0152 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0636
Minimum - Maximum-0.063148044 - 2.16354
Average (Standard dev.)0.0033549978 (±0.012185872)
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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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
    • Protein or peptide: Synthetic antibody, anti-BRIL Fab fragment, Heavy chain
    • Protein or peptide: anti-BRIL Fab Nanobody
    • Protein or peptide: Synthetic antibody, anti-BRIL Fab fragment, Light chain
    • Protein or peptide: Vasopressin V2 receptor,Soluble cytochrome b562
  • Ligand: (R)-Tolvaptan

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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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Macromolecule #1: Synthetic antibody, anti-BRIL Fab fragment, Heavy chain

MacromoleculeName: Synthetic antibody, anti-BRIL Fab fragment, Heavy chain
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.539314 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCD

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Macromolecule #2: anti-BRIL Fab Nanobody

MacromoleculeName: anti-BRIL Fab Nanobody / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.654138 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
AQPAMAQVQL QESGGGLVQP GGSLRLSCAA SGRTISRYAM SWFRQAPGKE REFVAVARRS GDGAFYADSV QGRFTVSRDD AKNTVYLQM NSLKPEDTAV YYCAIDSDTF YSGSYDYWGQ GTQVTVSSLE DYKDDKHHHH HH

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Macromolecule #3: Synthetic antibody, anti-BRIL Fab fragment, Light chain

MacromoleculeName: Synthetic antibody, anti-BRIL Fab fragment, Light chain
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.541164 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: Vasopressin V2 receptor,Soluble cytochrome b562

MacromoleculeName: Vasopressin V2 receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 60.330078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAWSHPQF EKGGGSGGGS GGGSWSHPQF EKLEVLQGPD YKDDDDAAST TSAVPGHPSL PSLPSQSSQ ERPLDTRDPL LARAELALLS IVFVAVALSN GLVLAALARR GRRGHWAPIH VFIGHLCLAD LAVALFQVLP Q LAWKATDR ...String:
MKTIIALSYI FCLVFADYKD DDDAWSHPQF EKGGGSGGGS GGGSWSHPQF EKLEVLQGPD YKDDDDAAST TSAVPGHPSL PSLPSQSSQ ERPLDTRDPL LARAELALLS IVFVAVALSN GLVLAALARR GRRGHWAPIH VFIGHLCLAD LAVALFQVLP Q LAWKATDR FRGPDALCRA VKYLQMVGMY ASSYMILAMT LDRHRAICRP MLAYRHGSGA HWNRPVLVAW AFSLLLSLPQ LF IFAQRNV EGGSGVTDCW ACFAEPWGRR TYVTWIALMV FVAPTLGIAA CQVLIFREIH ASLVPGPSER PGGRRRGRRT GSP GEGAHV SAAVAKTVRM TLVIVVVYVL CWAPFFLVQL WAAWDPEAPL EGAPFVLLML LASLNSCTNP WIYASFSSSV SSEL RSLLC CARGRTPPSL GPQDESCTTA SSSLAKDTSS ARRQLADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDA QKAT PPKLEDKSPD SPEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLRARSTL

UniProtKB: Vasopressin V2 receptor, Soluble cytochrome b562

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Macromolecule #5: (R)-Tolvaptan

MacromoleculeName: (R)-Tolvaptan / type: ligand / ID: 5 / Number of copies: 1 / Formula: A1IT8
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

Concentration22 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
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: 171151
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)

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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
Output model

PDB-9hap:
Cryo-EM structure of inactive human arginine-vasopressin (AVP) V2 receptor (V2R) with tolvaptan

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