Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain
Homology modeling and examination of the effect of the D92E mutation on the H5N1 nonstructural protein NS1 effector domain
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DOI：
10.1007/s00894-007-0245-0
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发表时间：
2007-12-01
影响因子：
2.2
通讯作者：
Wang, Binghe
中科院分区：
文献类型：
--
作者：
Li, Minyong;Wang, Binghe
H5N1型流感病毒毒株通常在非结构蛋白NS1中携带D92E点突变。这种关键突变与毒力和/或细胞因子耐药性增加有关，但这种变化的结构含义尚不清楚。此外，NS1蛋白也可能是开发针对H5N1毒株的新型抗病毒药物的潜在靶点。因此，建立一个合理的H5N1 NS1三维模型对于了解毒力增加的分子基础和设计新型抗病毒药物具有重要意义。基于非H5N1 NS1蛋白的晶体结构，通过同源性建模、分子力学和分子动力学模拟建立了H5N1 NS1病毒模型。发现D92E突变可导致羧酸侧链与其他磷酸化残基的相互作用减弱，从而激活NS1的磷酸化。
Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1.