近日，美国斯坦福大学K. Christopher Garcia及其研究团队解析出BILF1组成活性和免疫调节特性的结构基础。相关论文于2021年7月2日在线发表在《免疫》杂志上。

研究人员表示，EB病毒（EBV）编码称为BILF1的G蛋白偶联受体（GPCR），它对于EBV介导的免疫抑制和肿瘤发生至关重要。BILF1与抑制性G蛋白（Gi，人类趋化因子受体的主要细胞内信号传导效应器）结合，并表现出组成型信号传导活性；但BILF1的配体未知。

通过确定与Gi异源三聚体结合的BILF1结构，研究人员解析了BILF1组成型活性的起源。3.2Å分辨率的冷冻电镜结构揭示了BILF1内的一个细胞外环，它阻断了典型的趋化因子结合位点，这表明配体自主受体激活。相反，标志性配体激活的A类GPCR“微开关”处BILF1跨膜区域内的氨基酸取代稳定了组成型活性BILF1构象，从而以不依赖于配体的方式进行Gi偶联。因此，BILF1的组成性活性促进免疫抑制和毒力，与配体可用性无关，对相关病毒编码的GPCR功能和EBV的治疗靶向具有影响。

附：英文原文

Title: Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1

Author: Naotaka Tsutsumi, Qianhui Qu, Maa Mavri, Maibritt S. Baggesen, Shoji Maeda, Deepa Waghray, Christian Berg, Brian K. Kobilka, Mette M. Rosenkilde, Georgios Skiniotis, K. Christopher Garcia

Issue&Volume: 2021-07-02

Abstract: Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 coupleswith inhibitory G protein (Gi), the major intracellular signaling effector for humanchemokine receptors, and exhibits constitutive signaling activity; the ligand(s) forBILF1 are unknown. We studied the origins of BILF1’s constitutive activity throughstructure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer.The 3.2- resolution cryo-electron microscopy structure revealed an extracellularloop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomousreceptor activation. Rather, amino acid substitutions within BILF1 transmembrane regionsat hallmark ligand-activated class A GPCR “microswitches” stabilized a constitutivelyactive BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, theconstitutive activity of BILF1 promotes immunosuppression and virulence independentof ligand availability, with implications for the function of GPCRs encoded by relatedviruses and for therapeutic targeting of EBV.

DOI: 10.1016/j.immuni.2021.06.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00245-4