Structural Studies on Prokaryotic Potassium Channels

原核生物钾通道的结构研究

基本信息

批准号：
8396381
负责人：
Adrian Gross
金额：
$ 32.2万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8396381
关键词：
Action Potentials Address Adverse drug effect Adverse effects Affinity Anti-Arrhythmia Agents Archaea Arginine Arrhythmia Binding Biochemistry Biological Assay Biological Models Calcium Channel Cell membrane Cells Cessation of life Characteristics Clinical Medicine Complex Cysteine Data Dependence Detergents Development Device or Instrument Development Disease Drug Targeting Drug usage Electron Spin Resonance Spectroscopy Electrophysiology (science)Environment Epilepsy Essential Drugs Functional disorder Generations Goals Heart Human body Individual Intervention Ion Channel Ions Laboratories Lipid Bilayers Lipids Membrane Membrane Potentials Membrane Proteins Molecular Mutagenesis Neurosciences Nucleotides Peripheral Peripheral Nervous System Pharmaceutical Preparations Phylogenetic Analysis Physiology Potassium Potassium Channel Potassium Channel Binding Potassium Channel Blockers Process Property Proteins Proxy Resolution Rest Seminal Side Signal Transduction Site Sodium Channel Spin Labels Structural Models Structure Study models Tissues Water Work X-Ray Crystallography base drug development electron density improved novel prokaryotic potassium channel public health relevance receptor sensor tool voltage

项目摘要

DESCRIPTION (provided by applicant): Ion channels are instrumental in the generation of membrane potential, receptor potential, and action potential. They are the molecular building blocks for what is an essential characteristic of many cells in neuroscience: excitability. These proteins are implicated in the physiology and pathophysiology of all excitable tissues, underlie many disease processes including epilepsies and arrhythmias, and are major targets of essential drugs used in clinical medicine. Potassium channels are the phylogenetic founders of a large superfamily of structurally related ion channels that includes nucleotide gated channels, sodium channels, and calcium channels. Potassium channels are typically assembled from four identical subunits in a four-fold symmetrical fashion. This rather simple structural blueprint and the substantial practical advantage of only one subunit type have made potassium channels a much studied model system. This proposal explores two aspects of potassium channels: drug binding and voltage- dependence. In aim 1 we will determine the structural basis of the drug-channel interaction. In aim 2 we will attempt to describe the voltage-sensing domain of the channel in its native form. We will use a combination of cysteine mutagenesis, biochemistry, electrophysiology, site-directed spin labeling, and X-ray crystallography to study two prokaryotic potassium channels: KcsA and KvAP. The long-term goal of this proposal is to understand functional properties of ion channels at a structural level.

描述（由申请人提供）：离子通道有助于产生膜电位，受体电位和动作电位。它们是许多细胞在神经科学中的基本特征的分子构建块：兴奋性。这些蛋白质与所有令人兴奋的组织的生理和病理生理学有关，这是许多疾病过程，包括癫痫和心律不齐，是临床医学中使用的必需药物的主要靶标。钾通道是包括核苷酸门控通道，钠通道和钙通道的大型超家族的系统发育创始人。钾通道通常以四倍的对称方式从四个相同的亚基组装。这种相当简单的结构蓝图和只有一种亚基类型的实质性实践优势使钾通道成为了众所周知的模型系统。该建议探讨了钾通道的两个方面：药物结合和电压依赖性。在AIM 1中，我们将确定药物通道相互作用的结构基础。在AIM 2中，我们将尝试以其天然形式描述通道的电压感应域。我们将使用半胱氨酸诱变，生物化学，电生理学，定向的自旋标记和X射线晶体学的组合来研究两个原核生物钾通道：KCSA和KVAP。该建议的长期目标是了解结构层面离子通道的功能特性。