STRUCTURE AND FUNCTION OF MECHANOSENSITIVE ION CHANNELS

机械敏感离子通道的结构和功能

• 批准号: 6525996
• 负责人: DENNIS A DOUGHERTY
• 金额: $ 88.27万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525996
• 关键词: membrane channels; peptide chemical synthesis; protein engineering; protein structure function

The Program Project Grant Structure and Function of Mechanosensitive Ion Channels brings together an array of technologies drawn from chemistry, biology, physics, and biotechnology to develop the most detailed structure/function analysis of an ion channel protein to date. Building on the foundation of the high resolution crystal structure of the Tb-MscL channel reported by Rees, the tools of structural biology, organic chemistry, determine how a channel responds to a stimulus and translates that stimulus into an observable signal. The four key components of the proposed program are: structure, function, synthesis, and redesign, and each of the parent MscL channel and on selected variants with the ultimate goal being a structure determination of the open state of the channel. High resolution electrophysiology techniques will correlate structure and function, and single molecule spectroscopy will provide unprecedented views of ion behavior. For the first time, total diversity involving both natural and unnatural modifications. A high throughput assay for MscL behavior will greatly aid the analysis of the structural variants prepared, and computer modeling will provide detailed insights into experimental observations. Since ion channels lie at the core of molecular neurobiology, the information obtained from this Project Grant will have far-reaching consequences. The list of neurological disorders associated with a malfunction in an ion channel protein is long and growing, and the information obtained here will be invaluable in understanding such disease states and in developing effective treatment strategies.

该计划资助的机械敏感离子通道的结构和功能汇集了一系列来自化学、生物学、物理学和生物技术的技术，以开发迄今为止最详细的离子通道蛋白结构/功能分析。在 Rees 报告的 Tb-MscL 通道高分辨率晶体结构的基础上，结构生物学、有机化学工具确定通道如何响应刺激并将刺激转化为可观察的信号。所提议程序的四个关键组成部分是：结构、功能、综合和重新设计，以及每个父 MscL 通道和选定的变体，最终目标是确定通道打开状态的结构。高分辨率电生理学技术将关联结构和功能，单分子光谱将提供前所未有的离子行为视图。首次涉及自然和非自然修饰的全面多样性。 MscL 行为的高通量测定将极大地帮助分析所制备的结构变体，并且计算机建模将为实验观察提供详细的见解。由于离子通道是分子神经生物学的核心，因此从该项目资助中获得的信息将产生深远的影响。与离子通道蛋白功能障碍相关的神经系统疾病的清单很长，而且还在不断增加，这里获得的信息对于了解此类疾病状态和制定有效的治疗策略将具有无价的价值。