20.500.12556/RUL-137938 Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1 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. Epstein-Barr virus G protein G protein-coupled receptor GPCR cryo-EM immune evasion ligand-indpendent signaling receptor signaling viral GPCR true false true Angleški jezik Ni določen Članek v reviji 2022-07-06 11:51:16 2022-07-06 11:51:16 2022-09-15 04:16:05 0000-00-00 00:00:00 2021 0 0 Str. 1405-1416 no. 7 Vol. 54 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 2021-01-01 636.09:616.9:578 1097-4180 10.1016/j.immuni.2021.06.001 110440195 Structural_-mavri.pdf Structural_-mavri.pdf 1 40C49CB20D0507BEE658182AB8CD88CC 8ba42881b16dc30f48430af50cd5e16288da96ba29b1c52d77efb2c4901be151 9ada9320-fd19-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=158068 https://www.sciencedirect.com/science/article/abs/pii/S1074761321002454?via%3Dihub 1 f6042e7c-fd10-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=158065 Veterinarska fakulteta 0 0 0