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- EMDB-64559: Cryo-EM structure of human V1aR bound with SRX246 at a resolution... -

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Basic information

Entry
Database: EMDB / ID: EMD-64559
TitleCryo-EM structure of human V1aR bound with SRX246 at a resolution of 2.6 angstrom
Map dataEM_map
Sample
  • Complex: V1aR_dimer
    • Protein or peptide: Vasopressin V1a receptor
  • Ligand: SRX246
  • Ligand: CHOLESTEROL
  • Ligand: water
KeywordsGPCR / small molecule / antagonist / nanobody / SIGNALING PROTEIN
Function / homology
Function and homology information


Defective AVP does not bind AVPR1A,B and causes neurohypophyseal diabetes insipidus (NDI) / maternal aggressive behavior / cellular response to water deprivation / V1A vasopressin receptor binding / negative regulation of transmission of nerve impulse / sperm ejaculation / negative regulation of female receptivity / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity ...Defective AVP does not bind AVPR1A,B and causes neurohypophyseal diabetes insipidus (NDI) / maternal aggressive behavior / cellular response to water deprivation / V1A vasopressin receptor binding / negative regulation of transmission of nerve impulse / sperm ejaculation / negative regulation of female receptivity / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / myotube differentiation / positive regulation of prostaglandin biosynthetic process / telencephalon development / grooming behavior / maternal behavior / positive regulation of glutamate secretion / blood circulation / response to corticosterone / positive regulation of vasoconstriction / positive regulation of systemic arterial blood pressure / peptide hormone binding / social behavior / endocytic vesicle / positive regulation of heart rate / transport across blood-brain barrier / cellular response to hormone stimulus / positive regulation of cellular pH reduction / protein kinase C binding / generation of precursor metabolites and energy / calcium-mediated signaling / positive regulation of cytosolic calcium ion concentration / positive regulation of cell growth / G alpha (q) signalling events / endosome / G protein-coupled receptor signaling pathway / positive regulation of cell population proliferation / plasma membrane
Similarity search - Function
Vasopressin V1A receptor / Vasopressin V1 receptor, C-terminal / Vasopressin V1 receptor, C-terminal / DUF1856 / Vasopressin receptor / 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
Vasopressin V1a receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsWu XW / Zhong PY / Chu BX
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)32471303 China
CitationJournal: Nat Commun / Year: 2026
Title: Molecular basis of antagonism of the dimeric human arginine vasopressin receptor 1A.
Authors: Peiyu Zhong / Bingxin Chu / Zijing Yu / Yu Qiao / Yu Ding / Yongdeng Zhang / Xudong Wu /
Abstract: Arginine vasopressin (AVP) and oxytocin (OT) are peptide hormones critical for various physiological processes. Vasopressin receptor 1 A (V1aR), a primary AVP target, is promising for central ...Arginine vasopressin (AVP) and oxytocin (OT) are peptide hormones critical for various physiological processes. Vasopressin receptor 1 A (V1aR), a primary AVP target, is promising for central nervous system (CNS) disorders therapies, yet the mechanisms of antagonism and oligomerization remain poorly understood. Here, we present structures of human V1aR in its apo state and in complexes with antagonists: atosiban, balovaptan, and SRX246. Structural analyses reveal a dimeric V1aR assembly, validated by functional assays and imaging in cells. The apo structure shows a flat extracellular loop 2 (ECL2) with unpaired cysteines, undergoing significant conformational changes upon ligand binding. Antagonist-bound structures, combined with mutagenesis and radioligand binding assays, uncover distinct binding modes and key determinants for antagonism and selectivity. These findings provide a comprehensive understanding of V1aR assembly and dynamic regulation, offering valuable insights for structure-guided development of new antagonists targeting dimeric V1aR for CNS disorders.
History
DepositionMay 12, 2025-
Header (metadata) releaseFeb 4, 2026-
Map releaseFeb 4, 2026-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64559.png

Downloads & links

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Map

FileDownload / File: emd_64559.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM_map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 330 pix.
= 303.6 Å		0.92 Å/pix.
x 330 pix.
= 303.6 Å		0.92 Å/pix.
x 330 pix.
= 303.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.27
Minimum - Maximum-1.8855028 - 2.7568195
Average (Standard dev.)-0.0003590443 (±0.041688133)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 303.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A

Fileemd_64559_half_map_1.map
Annotationhalf_map_A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_64559_half_map_2.map
Annotationhalf_map_B
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : V1aR_dimer

EntireName: V1aR_dimer
Components
  • Complex: V1aR_dimer
    • Protein or peptide: Vasopressin V1a receptor
  • Ligand: SRX246
  • Ligand: CHOLESTEROL
  • Ligand: water

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Supramolecule #1: V1aR_dimer

SupramoleculeName: V1aR_dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Vasopressin V1a receptor

MacromoleculeName: Vasopressin V1a receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.69509 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EALGEGNGPP RDVRNEELAK LEIAVLAVTF AVAVLGNSSV LLALHRTPRK TSRMHLFIRH LSLADLAVAF FQVLPQMCWD ITYRFRGPD WLCRVVKHLQ VFGMFASAYM LVVMTADRYI AVCHPLKTLQ QPARRSRLMI AAAWVLSFVL STPQYFVFSM I EVNNVTKA ...String:
EALGEGNGPP RDVRNEELAK LEIAVLAVTF AVAVLGNSSV LLALHRTPRK TSRMHLFIRH LSLADLAVAF FQVLPQMCWD ITYRFRGPD WLCRVVKHLQ VFGMFASAYM LVVMTADRYI AVCHPLKTLQ QPARRSRLMI AAAWVLSFVL STPQYFVFSM I EVNNVTKA RDCWATFIQP WGSRAYVTWM TGGIFVAPVV ILGTCYGFIC YNIWCNVRGK TASRQSKGAE QAGVAFQKGF LL APCVSSV KSISRAKIRT VKMTFVIVTA YIVCWAPFFI IQMWSVWDPM SVWTESENPT ITITALLGSL NCCCKPWIYM FFS GHLLQD CVQSFPCCQN MKEKFNKEDT DSMSRRQTFY SNNRSPTNST GMWKDSPKSS KSIKFIPVST

UniProtKB: Vasopressin V1a receptor

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Macromolecule #2: SRX246

MacromoleculeName: SRX246 / type: ligand / ID: 2 / Number of copies: 2 / Formula: A1EQN
Molecular weightTheoretical: 703.869 Da

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 8 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 227014
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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