Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA.
Protein Sci. 2012 Nov;21(11):1620-33. doi: 10.1002/pro.2158. Epub 2012 Oct 9.
The influenza M2 protein forms an acid-activated and drug-sensitive proton channel in the virus envelope that is important for the virus lifecycle. The functional properties and high-resolution structures of this proton channel have been extensively studied to understand the mechanisms of proton conduction and drug inhibition. We review biochemical and electrophysiological studies of M2 and discuss how high-resolution structures have transformed our understanding of this proton channel. Comparison of structures obtained in different membrane-mimetic solvents and under different pH using X-ray crystallography, solution NMR, and solid-state NMR spectroscopy revealed how the M2 structure depends on the environment and showed that the pharmacologically relevant drug-binding site lies in the transmembrane (TM) pore. Competing models of proton conduction have been evaluated using biochemical experiments, high-resolution structural methods, and computational modeling. These results are converging to a model in which a histidine residue in the TM domain mediates proton relay with water, aided by microsecond conformational dynamics of the imidazole ring. These mechanistic insights are guiding the design of new inhibitors that target drug-resistant M2 variants and may be relevant for other proton channels.
流感 M2 蛋白在病毒包膜中形成一种酸激活和药物敏感的质子通道，对病毒生命周期至关重要。为了了解质子传导和药物抑制的机制，人们对该质子通道的功能特性和高分辨率结构进行了广泛研究。我们回顾了 M2 的生化和电生理学研究，并讨论了高分辨率结构如何改变我们对该质子通道的理解。使用 X 射线晶体学、溶液 NMR 和固态 NMR 光谱学，比较在不同的膜模拟溶剂中和不同 pH 值下获得的结构，揭示了 M2 结构如何取决于环境，并表明具有药理相关性的药物结合位点位于跨膜（TM）孔中。使用生化实验、高分辨率结构方法和计算建模评估了质子传导的竞争模型。这些结果趋于一个模型，即 TM 结构域中的组氨酸残基通过与水的质子传递，咪唑环的微秒构象动力学提供辅助。这些机制见解为设计针对耐药 M2 变体的新型抑制剂提供了指导，这些抑制剂可能与其他质子通道有关。
