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PLoS Pathog:解析流感病毒核酸内切酶三维结构有助开发新的抗流感药物

来源:生物谷 2012-08-04 15:36

来自法国格勒诺布尔欧洲分子生物学实验室(European Molecular Biology Laboratory, EMBL)的研究人员确定流感病毒RNA聚合酶中核酸内切酶部分的三维详细结构,其中这种酶在流感病毒复制当中发挥着关键作用。2012年8月2日,这种重要的发现在线发表在PLoS Pathogens期刊上。

研究人员集中关注这种病毒RNA聚合酶中核酸内切酶那部分。这种核酸内切酶负责一种独特的被称作“抢帽(cap-snatching)”的机制,从而允许流感病毒欺骗它的宿主细胞来产生病毒蛋白。在人细胞中,mRNA链的翻译成蛋白需要一种被称作“帽子(cap)”的特殊结构,其中这种帽子结构位于每个mRNA的始端。当流感病毒感染宿主细胞时,它的核酸内切酶抢夺来自宿主细胞自己的mRNA上的帽子结构。流感病毒RNA聚合酶的另一部分然后利用它作为合成病毒mRNA的起点。利用起始处正确的帽子结构,病毒mRNA然后能够劫持病毒感染细胞的蛋白产生装置来制造病毒蛋白,接着这些病毒蛋白组装到新的病毒当中从而继续扩散病毒感染。

法国格勒诺布尔欧洲分子生物学实验室主任Stephen Cusack领导的一个研究团队利用欧洲同步辐射装置(European Synchrotron Radiation Facility, ESRF)产生的高强度X射线束,分析了2009年大流行流感病毒毒株的核酸内切酶晶体。研究人员能够确定这种酶的三维原子结构,从而能够可视化观察几种不同小分子抑制物如何结合和阻断它的活性部位。如果核酸内切酶活性位点被抑制物阻断,这种酶就不能结合到它的正常底物上,即宿主细胞mRNA,因而也就能阻止病毒复制。

核酸内切酶活性位点的形状类似于一种洞穴,在它的底部含有两个金属离子。Cusack和同事们发现他们研究的所有抑制物结合到这两种金属离子上,但是根据它们的形状,不同的抑制物不同地结合到洞穴壁上的氨基酸。基于这种重要的详细结构信息,它将有助于科学家们设计新药物开对抗所有不同的流感病毒毒株,以便在未来5到10年内潜在地开发出一类新的抗流感病毒药物。(生物谷:Bioon.com)

本文编译自Catching the cap-snatcher: Structural analysis opens the way to new anti-influenza drugs

Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase

Eva Kowalinski1,2¤a, Chloe Zubieta1,2¤b, Andrea Wolkerstorfer3, Oliver H. J. Szolar3, Rob W. H. Ruigrok2, Stephen Cusack

It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative to current drug options in order to be able to treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, is an attractive target for antiviral drugs since potent polymerase inhibitors could directly stop viral replication at an early stage. Recent structural studies on functional domains of the heterotrimeric polymerase, which comprises subunits PA, PB1 and PB2, open the way to a structure based approach to optimise inhibitors of viral replication. In particular, the unique cap-snatching mechanism of viral transcription can be inhibited by targeting either the PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures of the 2009 pandemic H1N1 (pH1N1) PA endonuclease domain with a series of specific inhibitors, including four diketo compounds and a green tea catechin, all of which chelate the two critical manganese ions in the active site of the enzyme. Comparison of the binding mode of the different compounds and that of a mononucleotide phosphate highlights, firstly, how different substituent groups on the basic metal binding scaffold can be orientated to bind in distinct sub-pockets within the active site cavity, and secondly, the plasticity of certain structural elements of the active site cavity, which result in induced fit binding. These results will be important in optimising the design of more potent inhibitors targeting the cap-snatching endonuclease activity of influenza virus polymerase.

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