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- EMDB-43717: Cryo-EM Structure of KSHV ORF74 Apo Dimer at 2.8A -

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Basic information

Entry
Database: EMDB / ID: EMD-43717
TitleCryo-EM Structure of KSHV ORF74 Apo Dimer at 2.8A
Map dataCryo-EM Structure of KSHV ORF74 Apo Dimer at 2.8A
Sample
  • Complex: KSHV ORF74 (vGPCR) Apo Inverted Dimer
    • Protein or peptide: viral G-protein coupled receptor
KeywordsKSHV vGPCR / Viral GPCR / KSHV ORF74 / ORF74 Apo / ORF74 Inactive / VIRAL PROTEIN
Function / homology
Function and homology information


C-C chemokine receptor activity / C-C chemokine binding / cell chemotaxis / calcium-mediated signaling / positive regulation of cytosolic calcium ion concentration / immune response / host cell plasma membrane / membrane
Similarity search - Function
: / 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
viral G-protein coupled receptor
Similarity search - Component
Biological speciesHuman gammaherpesvirus 8
Methodsingle particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsSahoo B / Seo HD / Dai X / Jung J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA251275 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for ligand promiscuity and high signaling activity of Kaposi's Sarcoma-associated Herpesvirus-encoded GPCR.
Authors: Jun Bae Park / Bibekananda Sahoo / Amita Rani Sahoo / Dokyun Kim / Hogyu David Seo / James Bowman / Mi-Jeong Kwak / Sophia Suh / Matthias Buck / Xinghong Dai / Jae U Jung /
Abstract: Kaposi's Sarcoma-associated Herpesvirus encodes ORF74, a viral G protein-coupled receptor homologous to CXCR2, which plays a crucial role in Kaposi's Sarcoma development through its high basal ...Kaposi's Sarcoma-associated Herpesvirus encodes ORF74, a viral G protein-coupled receptor homologous to CXCR2, which plays a crucial role in Kaposi's Sarcoma development through its high basal signaling activity. Our cryoEM analysis of ORF74 in ligand-free, BRIL-fused ligand-free, and CXCL1/Gi-bound forms elucidates its ligand-independent signaling activity. A widely open, static extracellular cavity facilitates ligand promiscuity by enabling dynamic access and diverse binding modes. Structural alterations in CWxP, E/DRY, and NPxxY micro-switches stabilize the active conformation, leading to constitutive signaling. Metadynamics simulations reveal a dynamic ensemble between local switch structures corresponding to the inactive and active states, supporting spontaneous activation. CXCR2-ORF74 chimeras highlight intracellular loops 2 and 3 as key modulators of basal and agonist-induced activity. This study defines the structural basis of ORF74's ligand promiscuity, spontaneous activation, and high basal signaling, providing insights into its role in viral oncogenesis.
History
DepositionFeb 15, 2024-
Header (metadata) releaseAug 27, 2025-
Map releaseAug 27, 2025-
UpdateOct 8, 2025-
Current statusOct 8, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43717.png

Downloads & links

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Map

FileDownload / File: emd_43717.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM Structure of KSHV ORF74 Apo Dimer at 2.8A
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 360 pix.
= 237.6 Å		0.66 Å/pix.
x 360 pix.
= 237.6 Å		0.66 Å/pix.
x 360 pix.
= 237.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-2.2593117 - 2.788798
Average (Standard dev.)-0.00003260271 (±0.052411694)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 237.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: KSHV ORF74 Apo Dimer Cryo-EM Half Map B

Fileemd_43717_half_map_1.map
AnnotationKSHV ORF74 Apo Dimer Cryo-EM Half Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: KSHV ORF74 Apo Dimer Cryo-EM Half Map A

Fileemd_43717_half_map_2.map
AnnotationKSHV ORF74 Apo Dimer Cryo-EM Half Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : KSHV ORF74 (vGPCR) Apo Inverted Dimer

EntireName: KSHV ORF74 (vGPCR) Apo Inverted Dimer
Components
  • Complex: KSHV ORF74 (vGPCR) Apo Inverted Dimer
    • Protein or peptide: viral G-protein coupled receptor

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Supramolecule #1: KSHV ORF74 (vGPCR) Apo Inverted Dimer

SupramoleculeName: KSHV ORF74 (vGPCR) Apo Inverted Dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Human gammaherpesvirus 8
Molecular weightTheoretical: 42.1 KDa

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Macromolecule #1: viral G-protein coupled receptor

MacromoleculeName: viral G-protein coupled receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Human gammaherpesvirus 8
Molecular weightTheoretical: 42.132266 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAAEDFLTIF LDDDESWNET LNMSGYDYSG NFSLEVSVCE MTTVVPYTWN VGILSLIFLI NVLGNGLVTY IFCKHRSRAG AIDILLLGI CLNSLCLSIS LLAEVLMFLF PNIISTGLCR LEIFFYYLYV YLDIFSVVCV SLVRYLLVAY STRSWPKKQS L GWVLTSAA ...String:
MAAEDFLTIF LDDDESWNET LNMSGYDYSG NFSLEVSVCE MTTVVPYTWN VGILSLIFLI NVLGNGLVTY IFCKHRSRAG AIDILLLGI CLNSLCLSIS LLAEVLMFLF PNIISTGLCR LEIFFYYLYV YLDIFSVVCV SLVRYLLVAY STRSWPKKQS L GWVLTSAA WLIALVLSGD ACRHRSRVVD PVSKQAMCYE NAGNMTADWR LHVRTVSVTA GFLLPLALLI LFYALTWCVV RR TKLQARR KVRGVIVAVV VLFFVFCFPY HVLNLLDTLL RRRWIRDSCY TRGLINVGLA VTSLLQALYS AVVPLIYSCL GSL FRQRMY GLFQSLRQSF MSGADYKDDD DKGRPLEVLF QGPHHHHHHH HHH

UniProtKB: viral G-protein coupled receptor

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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

Concentration10 mg/mL
BufferpH: 7.5 / Component - Concentration: 25.0 mM / Component - Formula: C8H18N2O4S / Component - Name: HPEPS
Details: 25 mM HEPES pH 7.5, 150 mM NaCl, 0.005% (w/v) LMNG, 0.0005% (w/v) CHS, 10% Glycerol (v/v)
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: AB-INITIO
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 697456
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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