He Xiao, Tao Weiyu, Kang Yunlu, Xu Jiaxuan, Liu Xiaoyu, Chen Lei
State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Cell Discov. 2025 Jun 17;11(1):57. doi: 10.1038/s41421-025-00803-2.
The Hepatitis B Virus (HBV) poses a significant health threat, causing millions of deaths each year. Hepatitis B surface antigen (HBsAg), the sole membrane protein on the HBV viral envelope, plays crucial roles in viral attachment to host cells and serves as the target for neutralizing antibodies (NAbs). Despite its functional and therapeutic significance, the mechanisms by which NAbs recognize HBsAg remain elusive. Here, we found that HBsAg proteins exist in distinct subtypes and are recognized by different groups of antibodies. Cryo-electron microscopy (Cryo-EM) structures of HBsAg dimers in complex with NAb Fab fragments reveal that the antigenic loop (AGL) of these distinct HBsAg types share a common structural core comprised of four β-strands. However, their surface structures exhibit unexpected polymorphism due to distinct disulfide bond linkages within the AGL region. This structural polymorphism determines the recognition of HBsAg by different groups of NAbs.
乙型肝炎病毒（HBV）对健康构成重大威胁，每年导致数百万人死亡。乙型肝炎表面抗原（HBsAg）是HBV病毒包膜上唯一的膜蛋白，在病毒与宿主细胞的附着过程中发挥关键作用，并作为中和抗体（NAbs）的靶点。尽管其具有功能和治疗意义，但NAbs识别HBsAg的机制仍不清楚。在这里，我们发现HBsAg蛋白存在不同的亚型，并被不同组别的抗体识别。与NAb Fab片段复合的HBsAg二聚体的冷冻电子显微镜（Cryo-EM）结构显示，这些不同类型的HBsAg的抗原环（AGL）共享一个由四条β链组成的共同结构核心。然而，由于AGL区域内不同的二硫键连接，它们的表面结构呈现出意想不到的多态性。这种结构多态性决定了不同组别的NAbs对HBsAg的识别。
