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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis for suppression of a host antiviral response by influenza A virus
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Structural basis for suppression of a host antiviral response by influenza A virus

机译：甲型流感病毒抑制宿主抗病毒应答的结构基础

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Influenza A viruses are responsible for seasonal epidemics and high mortality pandemics. A major function of the viral NS1A protein, a virulence factor, is the inhibition of the production of IFN-β mRNA and other antiviral mRNAs. The NS1A protein of the human influenza A/Udorn/72 (Ud) virus inhibits the production of these antiviral mRNAs by binding the cellular 30-kDa subunit of the cleavage and polyadenyl-ation specificity factor (CPSF30), which is required for the 3' end processing of all cellular pre-mRNAs. Here we report the 1.95-A resolution X-ray crystal structure of the complex formed between the second and third zinc finger domain (F2F3) of CPSF30 and the C-terminal domain of the Ud NS1A protein. The complex is a tetramer, in which each of two F2F3 molecules wraps around two NS1A effector domains that interact with each other head-to-head. This structure identifies a CPSF30 binding pocket on NS1A comprised of amino acid residues that are highly conserved among human influenza A viruses. Single amino acid changes within this binding pocket eliminate CPSF30 binding, and a recombinant Ud virus expressing an NS1A protein with such a substitution is attenuated and does not inhibit IFN-β pre-mRNA processing. This binding pocket is a potential target for antiviral drug development. The crystal structure also reveals that two amino acids outside of this pocket, F103 and M106, which are highly conserved ( > 99%) among influenza A viruses isolated from humans, participate in key hydrophobic interactions with F2F3 that stabilize the complex.
机译：甲型流感病毒是造成季节性流行和高死亡率大流行的原因。病毒NS1A蛋白的主要功能是一种毒性因子，它是抑制IFN-βmRNA和其他抗病毒mRNA的产生。人类流感A / Udorn / 72（Ud）病毒的NS1A蛋白通过结合裂解的细胞30 kDa亚基和聚腺苷酸化特异性因子（CPSF30）来抑制这些抗病毒mRNA的产生，这对于3终止所有细胞前mRNA的加工。在这里，我们报告了在CPSF30的第二个和第三个锌指结构域（F2F3）与Ud NS1A蛋白的C端结构域之间形成的复合物的1.95-A分辨率X射线晶体结构。该复合物是四聚体，其中两个F2F3分子各自包裹着两个NS1A效应子结构域，它们彼此头对头相互作用。该结构鉴定了NS1A上的CPSF30结合口袋，该口袋由在人类甲型流感病毒中高度保守的氨基酸残基组成。在该结合袋中的单个氨基酸变化消除了CPSF30结合，表达具有这种取代的NS1A蛋白的重组Ud病毒被减弱，并且不抑制IFN-β-mRNA前加工。该结合袋是抗病毒药物开发的潜在靶标。晶体结构还揭示了该口袋外部的两个氨基酸F103和M106在从人类分离的甲型流感病毒中高度保守（> 99％），与稳定该复合物的F2F3参与了关键的疏水相互作用。

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