STRUCTURE OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR

这项工作的主要远景目标是获得高分辨率X射线 烟碱型乙酰胆碱受体(AChRs)的晶体结构 该家族包括烟碱型乙酰胆碱(AChR)、甘氨酸、γ- 氨基丁酸A(GABAA)和5-羟色胺(5-HT3)受体。全 参与神经系统内的信号传输，并具有 在人类神经生理学和神经疾病中具有广泛的重要性。 AChRs在临床上尤其重要，因为它们在 重症肌无力、尼古丁成瘾和神经退行性疾病。 蛋白质化学、配基结合研究、电生理学和电子 对原生和克隆AChRs的显微镜研究结合起来阐明了一些 这些受体的结构和功能的各个方面。这个 然而，AChRs的晶体结构一直难以捉摸。这个 Alpha7 AChR是一种有吸引力的X射线结晶学候选材料 尼古丁受体，因为它具有简化的性质 只含有α7亚基类型的。 拟议的培训环境非常适合多学科 这个项目的性质。赞助商乔恩·林德斯特罗姆是 AChRs的生物学，其实验室特别擅长异源基因 乙酰胆碱受体的表达和功能分析。帕特里克·罗尔，X光片 结晶学家和该项目的合作者，具有丰富的 膜蛋白的结晶学。蛋白质设计的方法， 表达和结构分析补充了先前对 蛋白质磁共振波谱首席研究员。他们 将与整个家族离子通道具有普遍相关性，并将 他研究结构生物学的长期目标的基础 神经系统的离子通道。

The major long-range goal of this work is obtain high resolution X-ray crystallographic structures of nicotinic acetylcholine receptors (AChRs). This family includes nicotinic acetylcholine (AChR), glycine, gamma- aminobutyric acidA (GABAA), and 5-hydroxytryptamine (5-HT3) receptors. All are involved in signal transmission within the nervous system and have wide-ranging importance in human neurophysiology and neurological diseases. The AChRs are particularly important clinically because of their roles in myasthenia gravis, nicotine addiction, and neurodegenerative diseases. Protein chemistry, ligand binding studies, electrophysiology, and electron microscopy on native and cloned AChRs have combined to elucidate some aspects of the structure and function of these receptors. The crystallographic structures of the AChRs, however, has been elusive. The alpha7 AChR is an attractive candidate for X-ray crystallography of nicotinic receptors because it possesses the simplifying property of containing only the alpha7 type of subunit. The proposed training environment is well-suited to the multidisciplinary nature of this project. The sponsor, Jon Lindstrom is a leader in the biology of AChRs whose laboratory is especially skilled in heterologous expression and functional analysis of AChRs. Patrick loll, an X-ray crystallographer and a collaborator on the project, is experienced with the crystallography of membrane proteins. The methods of protein design, expression and structural analysis complement the previous training of the principle investigator in protein magnetic resonance spectroscopy. They will have general relevance to this entire family ion channels and will be the foundation for his long-range goal of studying the structural biology of ion channels of the nervous system.