Wandzik Joanna M, Kouba Tomas, Cusack Stephen
European Molecular Biology Laboratory, Grenoble 38042-Cedex 9, France.
Cold Spring Harb Perspect Med. 2021 Sep 1;11(9):a038372. doi: 10.1101/cshperspect.a038372.
Influenza polymerase (FluPol) plays a key role in the viral infection cycle by transcribing and replicating the viral genome. FluPol is a multifunctional, heterotrimeric enzyme with cap-binding, endonuclease, RNA-dependent RNA polymerase and polyadenylation activities. It performs its functions in the context of the viral ribonucleoprotein particle (RNP), wherein the template viral RNA is coated by multiple copies of viral nucleoprotein. Moreover, it interacts with a number of host proteins that are essential cofactors and, consequently, adaptive mutations in the polymerase are required for crossing the avian-human species barrier. In this review, we show how mechanistic understanding of how FluPol performs its multiple functions has greatly advanced over the last decade through determination of high-resolution structures by X-ray crystallography and cryo-electron microscopy. These have revealed not only the detailed architecture of FluPol but highlighted the remarkably conformational flexibility that is inherent to its functioning as a dynamic RNA synthesis machine. Structural studies are also underpinning current attempts to develop next-generation anti-influenza drugs that directly target FluPol.
流感病毒聚合酶（FluPol）通过转录和复制病毒基因组在病毒感染周期中发挥关键作用。FluPol是一种多功能异源三聚体酶，具有帽结合、核酸内切酶、RNA依赖性RNA聚合酶和聚腺苷酸化活性。它在病毒核糖核蛋白颗粒（RNP）的环境中发挥功能，其中模板病毒RNA被多个病毒核蛋白拷贝所覆盖。此外，它与许多作为必需辅助因子的宿主蛋白相互作用，因此，聚合酶中的适应性突变是跨越禽-人物种屏障所必需的。在这篇综述中，我们展示了在过去十年中，通过X射线晶体学和冷冻电子显微镜确定高分辨率结构，对FluPol如何执行其多种功能的机制理解有了很大进展。这些不仅揭示了FluPol的详细结构，还突出了其作为动态RNA合成机器发挥功能所固有的显著构象灵活性。结构研究也为当前开发直接靶向FluPol的下一代抗流感药物的尝试提供了支持。
