National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
Nat Commun. 2021 Jul 5;12(1):4134. doi: 10.1038/s41467-021-24458-1.
Junin virus (JUNV) causes Argentine hemorrhagic fever, a debilitating human disease of high mortality rates and a great risk to public health worldwide. Studying the L protein that replicates and transcribes the genome of JUNV, and its regulator Z protein should provide critical clues to identify therapeutic targets for disrupting the life cycle of JUNV. Here we report the 3.54 Å cryo-EM structure of the JUNV L protein complexed with regulator Z protein. JUNV L structure reveals a conserved architecture containing signature motifs found in other L proteins. Structural analysis shows that L protein is regulated by binding of Z protein at the RNA product exit site. Based on these findings, we propose a model for the role of Z protein as a switch to turn on/off the viral RNA synthesis via its interaction with L protein. Our work unveils the mechanism of JUNV transcription, replication and regulation, which provides a framework for the rational design of antivirals for combating viral infections.
胡宁病毒（JUNV）可引起阿根廷出血热，这是一种严重影响人类健康的高死亡率疾病，对全球公共卫生构成重大威胁。研究复制和转录 JUNV 基因组的 L 蛋白及其调节蛋白 Z 蛋白，应能提供关键性线索，以确定用于破坏 JUNV 生命周期的治疗靶标。在这里，我们报告了与调节蛋白 Z 蛋白复合的 JUNV L 蛋白的 3.54Å 冷冻电镜结构。JUNV L 结构揭示了一种保守的架构，其中包含在其他 L 蛋白中发现的特征基序。结构分析表明，L 蛋白通过结合 Z 蛋白在 RNA 产物出口处进行调节。基于这些发现，我们提出了一个模型，用于解释 Z 蛋白如何通过与 L 蛋白相互作用，作为开关来开启/关闭病毒 RNA 合成。我们的工作揭示了 JUNV 转录、复制和调节的机制，为对抗病毒感染的抗病毒药物的合理设计提供了框架。
