Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
Cell Rep. 2019 Mar 19;26(12):3360-3368.e5. doi: 10.1016/j.celrep.2019.02.062.
We previously reported a human monoclonal antibody, ZK2B10, capable of protection against Zika virus (ZIKV) infection and microcephaly in developing mouse embryos. Here, we report the structural features and mechanism of action of ZK2B10. The crystal structure at a resolution of 2.32 Å revealed that the epitope is located on the lateral ridge of DIII of the envelope glycoprotein. Cryo-EM structure with mature ZIKV showed that the antibody binds to DIIIs around the icosahedral 2-fold, 3-fold, and 5-fold axes, a distinct feature compared to those reported for DIII-specific antibodies. The binding of ZK2B10 to ZIKV has no detectable effect on viral attachment to target cells or on conformational changes of the E glycoprotein in the acidic environment, suggesting that ZK2B10 functions at steps between the formation of the fusion intermediate and membrane fusion. These results provide structural and mechanistic insights into how ZK2B10 mediates protection against ZIKV infection.
我们之前报道了一种人源单克隆抗体 ZK2B10，它能够预防寨卡病毒（ZIKV）感染和发育中的小鼠胚胎小头畸形。在这里，我们报告了 ZK2B10 的结构特征和作用机制。分辨率为 2.32 Å 的晶体结构显示，表位位于包膜糖蛋白 DIII 的侧脊上。带有成熟 ZIKV 的冷冻电镜结构显示，该抗体结合在二十面体 2 重轴、3 重轴和 5 重轴周围的 DIII，这与报道的 DIII 特异性抗体明显不同。ZK2B10 与 ZIKV 的结合对病毒与靶细胞的附着或 E 糖蛋白在酸性环境中的构象变化没有可检测到的影响，这表明 ZK2B10 的作用发生在融合中间产物形成和膜融合之间的步骤。这些结果提供了结构和机制方面的见解，说明 ZK2B10 如何介导对 ZIKV 感染的保护。
