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bioRxiv · 10.1101/2023.12.27.573477

Structural basis for constitutive activation and CXCL1 recognition of human herpesvirus 8-encoded G protein-coupled receptor KSHV-GPCR

Liu, A.·Liu, Y.·Llinas del Torrent Masachs, C.·Zhang, W.·Pardo, L.·Ye, R. D.
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Abstract

Kaposis sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposis Sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. KSHV-GPCR is also unique for its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent as well as constitutive activity of KSHV-GPCR through cryo-EM structural determination of KSHV-GPCR-Gi signaling complexes with and without bound CXCL1 chemokine ligand. Analysis of the apo-KSHV-GPCR-Gi structure, with an overall resolution of 2.81 [A], unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. This and other structural motifs serve to stabilize the constitutively-active KSHV-GPCR. The CXCL1-bound KSHV-GPCR-Gi structure was solved to an overall resolution of 3.01 [A], and showed a two-site binding of the chemokine by the receptor. Together with functional validations, this work shed light on the structural basis for constitutive as well as CXCL1-induced activation of KSHV-GPCR. The work also demonstrates evolutionary advantage in immune evasion by KSHV through its virally encoded chemokine receptor, with potential implications in developing therapeutic strategies for KSHV infection.

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Liu, A., Liu, Y., Llinas del Torrent Masachs, C., Zhang, W., Pardo, L., Ye, R. D.. 2023-12-28. Structural basis for constitutive activation and CXCL1 recognition of human herpesvirus 8-encoded G protein-coupled receptor KSHV-GPCR. https://doi.org/10.1101/2023.12.27.573477

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