The structural basis for an essential subunit interaction in influenza virus RNA polymerase
The structural basis for an essential subunit interaction in influenza virus RNA polymerase
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DOI：
10.1038/nature07225
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发表时间：
2008-08-28
期刊：
影响因子：
64.8
通讯作者：
Park, Sam-Yong
中科院分区：
文献类型：
--
作者：
Obayashi, Eiji;Yoshida, Hisashi;Park, Sam-Yong
甲型流感病毒是一种主要的人类和动物病原体，有可能造成灾难性的生命损失。病毒繁殖迅速，变异频繁，偶尔跨越物种屏障。最近在亚洲出现的与高致病性人类病毒相关的禽流感突出表明迫切需要新的有效治疗方法(1)。在这里，我们证明了病毒RNA聚合酶中亚基界面对病毒复制的重要性，从而提供了一组完全独立于表面抗原类型的新的潜在药物结合位点。目前还没有针对这种异三聚体聚合酶复合物的药物。所有三个亚基，PB1， PB2和PA，都是转录和复制所必需的（2-4）。PB1携带聚合酶活性位点，PB2包含带帽RNA识别结构域，PA参与功能复合物的组装（5-7），但迄今为止对它们的结构信息报道甚少（8-11）。我们描述了流感a RNA聚合酶的一个亚基（PA）的大片段与另一个亚基（PB1）的片段结合的晶体结构。PA的羧基末端结构域形成一个新的褶皱，并形成一个深的，高度疏水的凹槽，PB1的氨基末端残基可以通过形成一个3（10）螺旋嵌入其中。
Influenza A virus is a major human and animal pathogen with the potential to cause catastrophic loss of life. The virus reproduces rapidly, mutates frequently and occasionally crosses species barriers. The recent emergence in Asia of avian influenza related to highly pathogenic forms of the human virus has highlighted the urgent need for new effective treatments(1). Here we demonstrate the importance to viral replication of a subunit interface in the viral RNA polymerase, thereby providing a new set of potential drug binding sites entirely independent of surface antigen type. No current medication targets this heterotrimeric polymerase complex. All three subunits, PB1, PB2 and PA, are required for both transcription and replication(2-4). PB1 carries the polymerase active site, PB2 includes the capped- RNA recognition domain, and PA is involved in assembly of the functional complex(5-7), but so far very little structural information has been reported for any of them(8-11). We describe the crystal structure of a large fragment of one subunit ( PA) of influenza A RNA polymerase bound to a fragment of another subunit ( PB1). The carboxy- terminal domain of PA forms a novel fold, and forms a deep, highly hydrophobic groove into which the amino- terminal residues of PB1 can fit by forming a 3(10) helix.