Sun Cong, Fang Xin-Yan, Bu Guo-Long, Zhong Lan-Yi, Xie Chu, Zhao Ge-Xin, Sui Sen-Fang, Liu Zheng, Zeng Mu-Sheng
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Cryo-electron Microscopy Center, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
Cell Rep. 2025 Jan 28;44(1):115168. doi: 10.1016/j.celrep.2024.115168. Epub 2025 Jan 9.
Epstein-Barr virus (EBV) is an oncogenic virus associated with multiple lymphoid malignancies and autoimmune diseases. During infection in B cells, EBV uses its major glycoprotein gp350 to recognize the host receptor CR2, initiating viral attachment, a process that has lacked direct structural evidence for decades. In this study, we resolved the structure of the gp350-CR2 complex, elucidated their key interactions, and determined the site-specific N-glycosylation map of gp350. Our findings reveal that CR2 primarily binds to gp350 through an electrostatically complementary and glycan-free interface and that the diversity of key residues in CR2 across different species influences EBV host selectivity mediated by gp350. With the confirmed binding, we constructed a CR2-Fc antibody analog that targets the vulnerable site of gp350, demonstrating a potent neutralization effect against EBV infection in B cells. Our work provides essential structural insights into the mechanism of EBV infection and host tropism, suggesting a potential antiviral agent.
爱泼斯坦-巴尔病毒（EBV）是一种致癌病毒，与多种淋巴系统恶性肿瘤和自身免疫性疾病相关。在B细胞感染过程中，EBV利用其主要糖蛋白gp350识别宿主受体CR2，启动病毒附着，这一过程几十年来一直缺乏直接的结构证据。在本研究中，我们解析了gp350-CR2复合物的结构，阐明了它们的关键相互作用，并确定了gp350的位点特异性N-糖基化图谱。我们的研究结果表明，CR2主要通过静电互补且无聚糖的界面与gp350结合，并且不同物种间CR2中关键残基的多样性影响了由gp350介导的EBV宿主选择性。通过确认的结合，我们构建了一种靶向gp350脆弱位点的CR2-Fc抗体类似物，证明其对B细胞中EBV感染具有强大的中和作用。我们的工作为EBV感染机制和宿主嗜性提供了重要的结构见解，提示了一种潜在的抗病毒药物。
