荆门蜱虫病毒聚合酶NSP1的结构及催化特性研究

荆门病毒是一类新型病毒，与黄病毒具有较近的亲缘关系，近年来已陆续发现荆门病毒感染人类的证据并引起广泛关注。与单节段基因组的黄病毒不同，荆门病毒的基因组分为多个节段，但其编码的复制酶NSP1和NSP2则分别与黄病毒NS5和NS3同源性较高。其中NSP1同时具备甲基转移酶和依赖RNA的RNA聚合酶（RdRP）功能，在病毒基因组复制和加帽过程中发挥关键作用，因此是揭示荆门病毒本质特征及其与黄病毒进化关系的理想体系。本项目选取荆门病毒的代表种荆门蜱虫病毒（Jingmen tick virus，简称JMTV）的NSP1作为研究对象，结合结构生物学和酶学方法，研究NSP1的三维结构和催化特性。在结构研究中关注黄病毒NS5体现出的构象多样性和RdRP的从头合成机制，在酶学研究中聚焦JMTV在引发、延伸等合成关键环节中与其他从头合成型RdRP的异同，为病毒RdRP的多样性研究和相关疾病防控提供科学依据。

The Jingmen viruses are a class of emerging viruses, and are close relatives of the flaviviruses. In recent years, human infection by the Jingmen viruses has become evident, and has gained global attention. Different from the unsegmented flaviviruses, the Jingmen virus RNA genome has multiple segments, but its replication enzymes NSP1 and NSP2 are highly homologous to the flavivirus NS5 and NS3, respectively. NSP1 harbors both the methyltransferase and RNA-dependent RNA polymerase (RdRP) functions, playing essential roles in viral genome replication and capping, and is therefore an ideal system to reveal the fundamentals of Jingmen viruses and their evolutionary relationship with the flaviviruses. In this project, we choose the NSP1 protein of the Jingmen Tick virus (JMTV), the representative species of the Jingmen viruses, as the research subject. By combining structural biology and enzymology approaches, we seek to investigate the three-dimensional structure and catalytic characteristics of JMTV NSP1. In the structural study, we aim at the conformational diversity, which was evident in the flavivirus NS5, and the catalytic mechanism of the de novo RdRP synthesis. In the enzymology study, we focus on the comparison of NSP1 with other de novo viral RdRPs with respect to the mechanisms of polymerase initiation and elongation. Through this project, we hope to provide a scientific basis to the understandings of viral RdRP diversity and to the prevention and control of Jingmen virus related diseases.