DEVELPMENT OF DRUGS THAT TARGET THE M2 PROTON CHANNEL

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 AM2是一种同源四聚体的III型完整膜蛋白，含有一个小的N-末端周质结构域(23个残基)、一个单一的跨膜结构域(20个残基)和一个C-末端细胞质尾巴(53个残基)。AM2在低pH下被激活，并选择性地传导质子，而不是其他阳离子，如Na+，K+。AM2是金刚烷胺/金刚乙胺几十年来被证实用于治疗流感感染的药物靶点，但由于跨膜药物结合位点出现耐药突变，如S31N、V27A、L26F等，其有效性大大降低。了解药物如何与AM2结合以及药物结合和pH变化如何影响AM2的全球构象对于合理设计下一代抗流感小分子药物是绝对必要的。我们的目标是用15N和13C双标记样品确定AM2TM(19-49)在溶液洗涤剂胶束中的结构。

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. AM2 is a homotetrameric, type III integral membrane protein containing a small N-terminal periplasmic domain (23 residues), a single transmembrane domain (20 residues), and a C-terminal cytoplasmic tail (53 residues). AM2 is activated at low pH and selective conduct proton over other cations like Na+, k+. AM2 is a proved drug target of amantadine/rimantadine in treating influenza infection for decades, but its effectiveness is greatly diminished by emerging drug resistant mutants in the transmembrane drug binding site like S31N, V27A, L26F etc. Understanding how the drug binds to AM2 and how drug binding and pH change affect the global conformation of AM2 is absolutely necessary for rational design of next generation anti-influenza small molecule drugs. Our goal is to get a structure assignment of AM2TM (19-49) in solution detergent micelle using 15N and 13C double labeled sample.