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TitleStructural basis for ligand promiscuity and high signaling activity of Kaposi's Sarcoma-associated Herpesvirus-encoded GPCR.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8403, Year 2025
Publish dateSep 25, 2025
AuthorsJun 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 /
PubMed AbstractKaposi'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.
External linksNat Commun / PubMed:40998787 / PubMed Central
MethodsEM (single particle)
Resolution2.89 - 3.73 Å
Structure data

43717

8w1a

EMDB-43717, PDB-8w1a:
Cryo-EM Structure of KSHV ORF74 Apo Dimer at 2.8A
Method: EM (single particle) / Resolution: 2.89 Å

EMDB-43718: NU-refined consensus map of CXCL1-KSHV ORF74-Gi-scFv16 Complex
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-43720: Cryo-EM Map of KSHV ORF74-BRIL-BAK5-Nb complex at 3.7A
Method: EM (single particle) / Resolution: 3.73 Å

EMDB-48095: 3DFlex refined map of CXCL1-KSHV ORF74-Gi-scFv16 Complex
Method: EM (single particle) / Resolution: 2.98 Å

EMDB-48097: Local refined cryoEM map of CXCL1-KSHV ORF74 region
Method: EM (single particle) / Resolution: 3.6 Å

48100

9ejc

EMDB-48100, PDB-9ejc:
Cryo-EM Structure of CXCL1-KSHV ORF74-Gi-scFv16 Complex
Method: EM (single particle) / Resolution: 2.98 Å

Source
  • human gammaherpesvirus 8
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsVIRAL PROTEIN / KSHV vGPCR / Viral GPCR / KSHV ORF74 / ORF74 Apo / ORF74 Inactive / VIRAL PROTEIN/SIGNALING PROTEIN / ORF74-CXCL1 / ORF74 Active / CXCL1 bound ORF74 / KSHV ORF74-CXCL1-Gi-scFv16 / VIRAL PROTEIN-SIGNALING PROTEIN complex

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