Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405, USA.
Nat Commun. 2017 Mar 27;8:14762. doi: 10.1038/ncomms14762.
The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions to those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Overall, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication.
最近爆发的 Zika 病毒（ZIKV）已在 30 多个国家感染了超过 100 万人。ZIKV 使用病毒编码的复制蛋白复制其 RNA 基因组。非结构蛋白 5（NS5）包含用于 RNA 加帽的甲基转移酶和用于病毒 RNA 合成的聚合酶。在这里，我们报道了全长 NS5 及其聚合酶结构域在 3.0Å分辨率下的晶体结构。NS5 结构与相关的日本脑炎病毒的 NS5 蛋白具有惊人的相似性。甲基转移酶包含用于底物结合和活性位点的在线口袋。聚合酶中的关键残基位于与丙型肝炎病毒聚合酶起始复合物相似的位置。聚合酶构象受甲基转移酶的影响，这使其能够更有效地进行体外 RNA 合成延伸。总的来说，我们的研究结果将有助于未来对 ZIKV 感染的研究和 ZIKV 复制抑制剂的开发。
