Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance
Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance
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DOI：
10.1128/jvi.01129-13
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Gao, George F.
中科院分区：
文献类型：
--
作者：
Li, Qing;Qi, Jianxun;Gao, George F.
流感病毒神经氨酸酶H274 Y置换是与对最常用的流感药物奥司他韦的抗性相关的高度流行的氨基酸置换。以前的结构研究表明，组特异性252残基（组1中的Y252和组2中的T252）可能是H274Y抗性的关键因素。然而，H274Y仅在N1亚型中有报道，这表明必须有其他决定H274Y耐药性的关键残基。此外，我们发现NA血清型N3的成员也具有Y252，提出了一个关键问题，即H274 Y抗性是否也可能用于某些第2组NA。在这里，我们证明了H274Y取代导致N3的轻度奥司他韦耐药性。N3、N1及其274 Y变体的比较结构分析表明，残基296（N1中的H和其他血清型的非芳香族）与保守的W295的相互作用是奥司他韦耐药性的另一个重要决定因素。
The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue ( Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 ( H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance.