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- EMDB-62581: Mechanistic insights into the versatile stoichiometry and biased ... -

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Basic information

Entry
Database: EMDB / ID: EMD-62581
TitleMechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex
Map data
Sample
  • Complex: beta_apj
    • Protein or peptide: Beta-arrestin-scFv30
    • Protein or peptide: Apelin Receptor
  • Ligand: (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
  • Ligand: CHOLESTEROL
KeywordsAPJR / Beta-arrestin / GPCR / SIGNALING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsYue Y / Wu LJ / Xu F
Funding support1 items
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, 2024-
Header (metadata) releaseSep 17, 2025-
Map releaseSep 17, 2025-
UpdateSep 17, 2025-
Current statusSep 17, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62581.png

Downloads & links

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Map

FileDownload / File: emd_62581.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.0017292756 - 2.6182914
Average (Standard dev.)0.00069218554 (±0.019046446)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62581_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62581_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : beta_apj

EntireName: beta_apj
Components
  • Complex: beta_apj
    • Protein or peptide: Beta-arrestin-scFv30
    • Protein or peptide: Apelin Receptor
  • Ligand: (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
  • Ligand: CHOLESTEROL

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Supramolecule #1: beta_apj

SupramoleculeName: beta_apj / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Beta-arrestin-scFv30

MacromoleculeName: Beta-arrestin-scFv30 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.345 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTAA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPSSVTL QPGPEDTGKA IGVDYEVKAF VAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTAA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPSSVTL QPGPEDTGKA IGVDYEVKAF VAENLEEKIH K RNSVRLVI EKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD IVLFNTA QYKVPVAMEE ADDTVAPSST FSKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP EHETPVDTNL SDIQMTQSPS SLSASVGDRV TITC RASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYYC QQYKYVPVTF GQGTK VEIK GTTAASGSSG GSSSGAEVQL VESGGGLVQP GGSLRLSCAA SGFNVYSSSI HWVRQAPGKG LEWVASISSY YGYTYY ADS VKGRFTISAD TSKNTAYLQM NSLRAEDTAV YYCARSRQFW YSGLDYWGQG TLVTVSSA

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Macromolecule #2: Apelin Receptor

MacromoleculeName: Apelin Receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.609426 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHLEVLFQ GPADLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPK LEDKSPDSPE MKDFRHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLE EGGDFDNYYG A DNQSECEY ...String:
MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHLEVLFQ GPADLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPK LEDKSPDSPE MKDFRHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLE EGGDFDNYYG A DNQSECEY TDWKSSGALI PAIYMLVFLL GTTGNGLVLW TVFRSSREKR RSADIFIASL AVADLTFVVT LPLWATYTYR DY DWPFGTF ACKLSSYLIF VNMYASVFCL TGLSFDRYLA IVRPVANARL RLRVSGAVAT AVLWVLAALL AMPVMVLRTT GDL ENTTKV QCYMDYSMVA TVSSEWAWEV GLGVSSTTVG FVVPFTIMLT CYFFIAQTIA GHFRKERIEG LRKRRRLLSI IVVL VVTFA LCWMPYHLVK TLYMLGSLLH WPCDFDLFLM NIFPYCTCIS YVNSCLNPFL YAFFDPRFRQ ACTSMLCCGQ SRARG RTPP SLGPQDE(SEP)C(TPO) (TPO)A(SEP)(SEP)(SEP)LAKDT SS

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Macromolecule #3: (1~{S},2~{S})-~{N}-[4-(2,6-dimethoxyphenyl)-5-(6-methylpyridin-2-...

MacromoleculeName: (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
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1L6R
Molecular weightTheoretical: 525.58 Da

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 292664
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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