Solution NMR structure of the V27A drug resistant mutant of influenza A M2 channel.
Solution NMR structure of the V27A drug resistant mutant of influenza A M2 channel.
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DOI：
10.1016/j.bbrc.2010.09.008
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发表时间：
2010-10-08
影响因子：
3.1
通讯作者：
Chou JJ
中科院分区：
文献类型：
--
作者：
Pielak RM;Chou JJ
甲型流感病毒的M2蛋白形成了病毒复制所需的质子选择性通道；它也是抗流感药物金刚烷胺和金刚乙胺的靶标。然而，广泛存在的耐药突变极大地损害了这些药物的有效性。在这里，我们报告了高致病性、耐药突变体V27A的溶液核磁共振结构。这种结构揭示了与野生型的细微结构差异，这可能与耐药性有关。V27A突变显著减少了跨膜螺旋N端之间的疏水堆积，这解释了更松散、更动态的四聚体组装。在变构抑制模型的情况下，减弱的通道组件可以通过破坏Asp44处的金刚乙胺结合口袋的稳定性来抵抗药物结合，或者在孔阻断模型的情况下，通过减少与孔中金刚烷胺的疏水接触来抵抗药物结合。此外，V27A结构在N末端显示出显著增加的通道开放，这可能解释了观察到的该突变体更快的质子传导。此外，由于为V27A突变体记录的高质量的核磁共振数据，我们能够确定连接通道结构域和C末端两亲性螺旋的结构区域，这在野生型结构中没有确定。新的结构数据表明，两亲性螺旋与通道结构域结合得更紧密，为质子转移途径提供了新的见解。
The M2 protein of influenza A virus forms a proton-selective channel that is required for viral replication; it is also the target of the anti-influenza drugs, amantadine and rimantadine. Widespread drug-resistant mutants, however, has greatly compromised the effectiveness of these drugs. Here, we report the solution NMR structure of the highly pathogenic, drug resistant mutant V27A. The structure reveals subtle structural differences from wildtype that maybe linked to drug resistance. The V27A mutation significantly decreases hydrophobic packing between the N-terminal ends of the transmembrane helices, which explains the looser, more dynamic tetrameric assembly. The weakened channel assembly can resist drug binding either by destabilizing the rimantadine-binding pocket at Asp44, in the case of the allosteric inhibition model, or by reducing hydrophobic contacts with amantadine in the pore, in the case of the pore blocking model. Moreover, the V27A structure shows a substantially increased channel opening at the N-terminal end, which may explain the faster proton conduction observed for this mutant. Furthermore, due to the high quality NMR data recorded for the V27A mutant, we were able to determine the structured region connecting the channel domain to the C-terminal amphipathic helices that was not determined in the wildtype structure. The new structural data show that the amphipathic helices are packed much more closely to the channel domain and provide new insights into the proton transfer pathway.
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