8K4P

Cryo-EM structure of an active Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR) in complex with Gi protein

Summary for 8K4P

• Entry DOI: 10.2210/pdb8k4p/pdb
• EMDB information: 36889
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, G protein-coupled receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (4 entities in total)
• Functional Keywords: kaposi's sarcoma-associated herpesvirus-g protein-coupled receptor, kshv-gpcr, hhv8, viral protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 117032.59

Authors

Liu, Y.Z.,Liu, A.J. (deposition date: 2023-07-20, release date: 2024-07-24, Last modification date: 2025-07-02)

Primary citation

Liu, A.,Liu, Y.,Llinas Del Torrent Masachs, C.,Zhang, W.,Pardo, L.,Ye, R.D.
Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition.
Proc.Natl.Acad.Sci.USA, 121:e2403217121-e2403217121, 2024

PubMed Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. Like other herpesvirus-encoded GPCRs, KSHV-GPCR is characterized by its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent and constitutive activation of KSHV-GPCR, obtaining high-resolution cryo-EM structures of KSHV-GPCR-Gi complexes with and without the bound CXCL1 chemokine. Analysis of the apo-KSHV-GPCR-Gi structure (2.81 Å) unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. In comparison, the CXCL1-bound KSHV-GPCR-Gi structure (3.01 Å) showed a two-site binding mode and provided detailed information of CXCL1 binding to a chemokine receptor. The dual activation mechanism employed by KSHV-GPCR represents an evolutionary adaptation for immune evasion and contributes to the pathogenesis of Kaposi's sarcoma. Together with results from functional assays that confirmed the structural models, these findings may help to develop therapeutic strategies for KSHV infection.

PubMed: 39378089
DOI: 10.1073/pnas.2403217121

Experimental method

ELECTRON MICROSCOPY (2.81 Å)