STRUCTURAL STUDIES ON PROKARYOTIC POTASSIUM CHANNELS

原核钾通道的结构研究

• 批准号: 6151234
• 负责人: Adrian Gross
• 金额: $ 18.36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151234
• 关键词: Streptomyces; electron spin resonance spectroscopy; electrophysiology; lipid bilayer membrane; membrane model; membrane potentials; molecular cloning; potassium channel; prokaryote; protein folding; protein structure function; voltage gated channel

Voltage-dependent ion channels are instrumental in the generation of membrane potential, receptor potential, and action potential. They are implicated in the physiology and pathophysiology of all excitable tissues. These proteins underlie many disease processes including arrhythmias and epilepsies and are major targets of essential drugs used in clinical medicine. Despite the obvious biological and clinical importance of these proteins, very little is known about their structure. Obtaining this structural information is of paramount importance to a mechanistic understanding of their function. This proposal presents a new approach toward addressing the structure and function of these proteins. Bacterial model systems will be studied by two complimentary techniques: site-directed spin labeling and electrophysiology. The study will address two key properties of potassium channels: permeation and gating. It is thought that the structural elements underlying permeation and, to some extent, gating have been identified. All cation selective voltage-dependent ion channels share a common core domain that is sufficient for ion permeation. Also, a highly unusual transmembrane segment known as S4 has been implicated as part of the structural element responsible for voltage-dependent gating. These two structural elements will be studied with the two techniques. It is anticipated that the results of the spin labeling study will provide sufficient constraints to determine the structure of these two elements to the level of the backbone fold. The resulting folding model will provide the basis for a mechanistically inspired functional study using electrophysiology. The long-term goal of this proposal is to understand functional properties of ion channels at a structural level.

电压依赖性离子通道有助于产生 膜电位，受体电位和作用潜力。他们是 与所有兴奋的生理学和病理生理学有关 组织。 这些蛋白质是许多疾病过程的基础 心律不齐和癫痫病，是使用必需药物的主要靶标 临床医学。 尽管有明显的生物学和临床 这些蛋白质的重要​​性，对它们的知识知之甚少 结构。 获得这些结构信息至关重要 对于机械理解其功能的重要性。 该提案提出了一种解决结构的新方法 这些蛋白质的功能。 将研究细菌模型系统 通过两种免费技术：定向定向的自旋标签和 电生理学。 该研究将解决两个关键特性 钾通道：渗透和门控。 据认为 结构元素渗透并在某种程度上是门控的 已经确定了。 所有阳离子选择性电压依赖性离子 频道共享一个足以使离子的通用核心领域 渗透。 另外，一个高度不寻常的跨膜段称为S4 已被视为负责结构要素的一部分 电压依赖性门。 将研究这两个结构元素 使用两种技术。 预计自旋标记研究的结果将 提供足够的限制来确定这两个的结构 元素折叠的元素。 由此产生的折叠模型 将为机械灵感的功能研究提供基础 使用电生理学。 该提议的长期目标是 了解结构级别离子通道的功能特性。