Structural basis for ligand promiscuity and high signaling activity of Kaposi’s Sarcoma-associated Herpesvirus-encoded GPCR

Jun Bae Park, Bibekananda Sahoo, Amita Rani Sahoo, Dokyun Kim, Hogyu David Seo, James Bowman, Mi-Jeong Kwak, Sophia Suh, Matthias Buck (), Xinghong Dai () and Jae U. Jung ()
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Jun Bae Park: Lerner Research Institute, Cleveland Clinic
Bibekananda Sahoo: Case Western Reserve University
Amita Rani Sahoo: Case Western Reserve University
Dokyun Kim: Lerner Research Institute, Cleveland Clinic
Hogyu David Seo: Lerner Research Institute, Cleveland Clinic
James Bowman: Lerner Research Institute, Cleveland Clinic
Mi-Jeong Kwak: Lerner Research Institute, Cleveland Clinic
Sophia Suh: Lerner Research Institute, Cleveland Clinic
Matthias Buck: Case Western Reserve University
Xinghong Dai: Case Western Reserve University
Jae U. Jung: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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 signaling activity. Our cryoEM analysis of ORF74 in ligand-free, BRIL-fused ligand-free, and CXCL1/Gitrimer-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.

Date: 2025
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DOI: 10.1038/s41467-025-63457-4

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