TRANSMEMBRANE DOMAIN OF INFLUENZA A M2 PROTON CHANNEL

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 甲型流感病毒中的M2蛋白在跨膜结构域（TM）中具有离子通道活性，并且在病毒进入宿主期间是病毒体酸化和有效的病毒核糖核蛋白脱壳所需的。基于金刚烷的抗病毒药物金刚烷胺和金刚乙胺先前显示通过抑制M2通道活性有效治疗流感。我们最近确定了TM（野生型）在载脂蛋白和金刚烷胺结合形式的结构，分别在中等和低分辨率。阐明药物的抑制机制需要在原子水平上了解药物与蛋白质之间的相互作用，因此需要高分辨率的蛋白质-药物复合物结构。 在设计新型M2抑制剂方面，我们正致力于结晶耐药突变体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. M2 protein in influenza A virus has an ion channel activity in transmembrane domain (TM) and is required for the acidification of the virion and efficient viral ribonucleoprotein uncoating during viral entry into the host. Adamantane based antiviral drugs, amantadine and rimantadine were previously shown effective in treating influenza by inhibiting M2 channel activity. We have recently determined the structures of TM (wildtype) in apo and amantadine bound forms at medium and low resolutions respectively. Elucidation of inhibitory mechanism by drug needs the understanding of interactions between drug and protein at atomic level, thus there is a requirement of high resolution structures of protein-drug complexes. In the view of designing novel M2 inhibitors, we are working towards crystallizing drug resistance mutants.