7JHJ

Structure of the Epstein-Barr virus GPCR BILF1 in complex with human Gi

Summary for 7JHJ

• Entry DOI: 10.2210/pdb7jhj/pdb
• EMDB information: 22338
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: membrane protein, viral gpcr, class a-like gpcr, epstein-barr virus
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 148763.61

Authors

Tsutsumi, N.,Qu, Q.H.,Skiniotis, G.,Garcia, K.C. (deposition date: 2020-07-20, release date: 2021-07-07, Last modification date: 2024-10-30)

Primary citation

Tsutsumi, N.,Qu, Q.,Mavri, M.,Baggesen, M.S.,Maeda, S.,Waghray, D.,Berg, C.,Kobilka, B.K.,Rosenkilde, M.M.,Skiniotis, G.,Garcia, K.C.
Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1.
Immunity, 54:1405-1416.e7, 2021

PubMed Abstract: Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-Å resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches" stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.

PubMed: 34216564
DOI: 10.1016/j.immuni.2021.06.001

Experimental method

ELECTRON MICROSCOPY (3.2 Å)