State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, National Engineering Research Center for Non-food Biorefinery, Guangxi Academy of Sciences, Nanning, Guangxi 530007, China.
Curr Protein Pept Sci. 2012 May;13(3):205-10. doi: 10.2174/138920312800785030.
For quite a long period of time in history, many intense efforts have been made to determine the 3D (three-dimensional) structure of the M2 proton channel. The reason why the M2 proton channel has attracted so many attentions is because (1) it is the key for really understanding the life cycle of influenza viruses, and (2) it is indispensable for conducting rational drug design against the flu viruses. Recently, the long-sough 3D structures of the M2 proton channels for both influenza A and B viruses were consecutively successfully determined by the high-resolution NMR spectroscopy (Schnell J.R. and Chou, J.J., Nature, 2008, 451: 591-595; Wang, J., Pielak, R.M., McClintock, M.A., and Chou, J.J., Nature Structural & Molecular Biology, 2009,16: 1267-1271). Such a milestone work has provided a solid structural basis for in-depth understanding the action mechanism of the M2 channel and rationally designing effective drugs against influenza viruses. This review is devoted to, with the focus on the M2 proton channel of influenza A, addressing a series of relevant problems, such as how to correctly understand the novel allosteric inhibition mechanism inferred from the NMR structure that is completely different from the traditional view, what the possible impacts are to the previous functional studies in this area, and what kind of new strategy can be stimulated for drug development against influenza.
在历史的相当长一段时间里，人们付出了许多努力来确定 M2 质子通道的三维（3D）结构。M2 质子通道之所以引起如此多的关注，是因为（1）它是真正理解流感病毒生命周期的关键，（2）它是针对流感病毒进行合理药物设计所必不可少的。最近，高分辨率 NMR 光谱学连续成功地确定了流感 A 型和 B 型 M2 质子通道的长期以来备受期待的 3D 结构（Schnell J.R. 和 Chou，J.J.，自然，2008，451：591-595；Wang，J.，Pielak，R.M.，McClintock，M.A.和 Chou，J.J.，自然结构与分子生物学，2009，16：1267-1271）。这项里程碑式的工作为深入了解 M2 通道的作用机制和合理设计针对流感病毒的有效药物提供了坚实的结构基础。本综述专注于流感 A 型的 M2 质子通道，解决了一系列相关问题，例如如何正确理解从 NMR 结构推断出的全新变构抑制机制，该机制与传统观点完全不同，对该领域以前的功能研究有何可能的影响，以及针对流感病毒的药物开发可能会产生什么样的新策略。
