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- PDB-9kuv: Mechanistic insights into the versatile stoichiometry and biased ... -

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Basic information

Entry
Database: PDB / ID: 9kuv
TitleMechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex
Components
  • Apelin Receptor
  • Beta-arrestin-scFv30
KeywordsSIGNALING PROTEIN / APJR / Beta-arrestin / GPCR
Function / homology: / CHOLESTEROL
Function and homology information
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsYue, Y. / Wu, L.J. / Xu, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex.
Authors: Yang Yue / Chanjuan Xu / Lijie Wu / Man Na / Kexin Xu / Xuan Chen / Yuxuan Song / Sichun Weng / Lu Xu / Fei Li / Xi Lin / Arthur Wang / Jianfeng Liu / Fei Xu /
Abstract: The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health. Understanding the mechanisms of biased agonism at APJR is crucial for drug discovery, as stimulation ...The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health. Understanding the mechanisms of biased agonism at APJR is crucial for drug discovery, as stimulation of the β-arrestin pathway may lead to some adverse effects. Structural analyses of APJR-Gi complexes have clarified the structural basis of receptor dimerization and activation, yet the absence of structural data on APJR-arrestin complexes has impeded a comprehensive understanding of APJR stoichiometry in the dual signaling pathways and biased agonism. Here, we present APJR-β-arrestin1 structures bound to a clinical drug analog, revealing 2:2 and 2:1 stoichiometries associated with differential β-arrestin recruitment. Through comparison of the two transducer-coupled APJR structures bound to the same ligand, we identify key residues and motifs crucial for directing biased signaling. These findings highlight APJR's versatile stoichiometry in coupling with β-arrestin and Gi proteins, establishing a framework for understanding biased agonism and guiding the development of therapeutics.
History
DepositionDec 4, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 17, 2025Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data 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: Beta-arrestin-scFv30
R: Apelin Receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,8674
Polymers125,9542
Non-polymers9122
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody Beta-arrestin-scFv30


Mass: 68345.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#2: Protein Apelin Receptor


Mass: 57609.426 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#3: Chemical ChemComp-A1L6R / (1~{S},2~{S})-~{N}-[4-(2,6-dimethoxyphenyl)-5-(6-methylpyridin-2-yl)-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-oxidanyl-propane-2-sulfonamide


Mass: 525.580 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7O5S
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / 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: beta_apj / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 292664 / Symmetry type: POINT
RefinementHighest resolution: 3.21 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067331
ELECTRON MICROSCOPYf_angle_d0.6749988
ELECTRON MICROSCOPYf_dihedral_angle_d7.8351021
ELECTRON MICROSCOPYf_chiral_restr0.0421134
ELECTRON MICROSCOPYf_plane_restr0.0071237

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