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- PDB-9uwi: Cryo-EM structure of human V1aR bound with atosiban at a resoluti... -

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Basic information

Entry
Database: PDB / ID: 9uwi
TitleCryo-EM structure of human V1aR bound with atosiban at a resolution of 2.8 angstrom
Components
  • Atosiban
  • Vasopressin V1a receptor
KeywordsSIGNALING PROTEIN / GPCR / small molecule / antagonist / nanobody
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
CHOLESTEROL / Vasopressin V1a receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWu, X.W. / Zhong, P.Y. / Chu, B.X.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 28, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Vasopressin V1a receptor
B: Vasopressin V1a receptor
C: Atosiban
D: Atosiban
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,9278
Polymers89,3814
Non-polymers1,5474
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Vasopressin V1a receptor / V1aR / AVPR V1a / Antidiuretic hormone receptor 1a / Vascular/hepatic-type arginine vasopressin receptor


Mass: 43695.090 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AVPR1A, AVPR1 / Production host: Homo sapiens (human) / References: UniProt: P37288
#2: Protein/peptide Atosiban


Mass: 995.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
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: V1aR_dimer / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 340153 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044726
ELECTRON MICROSCOPYf_angle_d0.5566466
ELECTRON MICROSCOPYf_dihedral_angle_d9.795644
ELECTRON MICROSCOPYf_chiral_restr0.036750
ELECTRON MICROSCOPYf_plane_restr0.004752

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