Integrating computational modeling and functional assays to decipher the structure-function relationship of influenza virus PB1 protein.
Integrating computational modeling and functional assays to decipher the structure-function relationship of influenza virus PB1 protein.
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整合计算模型和功能测定来破译流感病毒PB1蛋白的结构-功能关系
DOI：
10.1038/srep07192
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发表时间：
2014-11-26
影响因子：
4.6
通讯作者：
Jiang T
中科院分区：
文献类型：
--
作者：
Li C;Wu A;Peng Y;Wang J;Guo Y;Chen Z;Zhang H;Wang Y;Dong J;Wang L;Qin FX;Cheng G;Deng T;Jiang T
流感病毒PB 1蛋白是异源三聚体聚合酶复合物（PA、PB 1和PB 2）的核心亚基，其中PB 1负责催化RNA聚合并与病毒RNA启动子结合。在这三个亚基中，PB 1是迄今为止就其结构信息而言知之最少的亚基。在这项工作中，通过整合基于模板的结构建模方法与所有已知的序列和功能信息的PB 1蛋白，我们构建了一个模型化的结构PB 1。基于此模型，我们进行了突变分析的关键残基，构成RNA模板结合和催化（TBC）通道中的RNP重建系统。结果与模型相关性良好，并进一步鉴定了PB 1的新残基，这些残基对RNA合成至关重要。此外，我们从PB 1序列中衍生出5个形成TBC通道的肽，其中4个可以抑制病毒RNA聚合酶活性。有趣的是，我们发现其中一个命名为PB 1（491-515）的基因可以通过破坏病毒RNA启动子聚合酶的结合活性来抑制流感病毒的复制。因此，本研究不仅加深了我们对PB 1结构与功能关系的理解，而且将促进新型流感病毒治疗药物的开发。
The influenza virus PB1 protein is the core subunit of the heterotrimeric polymerase complex (PA, PB1 and PB2) in which PB1 is responsible for catalyzing RNA polymerization and binding to the viral RNA promoter. Among the three subunits, PB1 is the least known subunit so far in terms of its structural information. In this work, by integrating template-based structural modeling approach with all known sequence and functional information about the PB1 protein, we constructed a modeled structure of PB1. Based on this model, we performed mutagenesis analysis for the key residues that constitute the RNA template binding and catalytic (TBC) channel in an RNP reconstitution system. The results correlated well with the model and further identified new residues of PB1 that are critical for RNA synthesis. Moreover, we derived 5 peptides from the sequence of PB1 that form the TBC channel and 4 of them can inhibit the viral RNA polymerase activity. Interestingly, we found that one of them named PB1(491–515) can inhibit influenza virus replication by disrupting viral RNA promoter binding activity of polymerase. Therefore, this study has not only deepened our understanding of structure-function relationship of PB1, but also promoted the development of novel therapeutics against influenza virus.
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影响因子：
158.5
作者：
Gao, Rongbao;Cao, Bin;Shu, Yuelong
通讯作者：
Shu, Yuelong
DOI：
10.1007/978-1-60761-842-3_6
发表时间：
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期刊：
Methods in molecular biology (Clifton, N.J.)
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