Structure/function of P2X receptors: ion access pathway and selectivity mechanism

P2X受体的结构/功能：离子进入途径和选择性机制

• 批准号: 8309016
• 负责人: Toshimitsu Kawate
• 金额: $ 24.64万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309016
• 关键词: Action Potentials; Affect; Anions; Architecture; Binding; Binding Sites; Calcium; Cardiovascular system; Cations; Charge; Chimera organism; Data; Disease; Electrostatics; Esthesia; Foundations; Gated Ion Channel; Goals; Human body; Inflammation; Inflammatory; Inflammatory Response; Instruction; Intervention; Ion Channel; Ions; Knowledge; Lateral; Lead; Ligand Binding; Measures; Mediating; Membrane; Molecular; Mutate; Nervous system structure; P2X-receptor; Pain; Pathway interactions; Pharmacology; Physiological; Play; Rattus; Receptor Activation; Research; Role; Sensory; Signal Transduction; Structure; Surface; System; Techniques; X-Ray Crystallography; base; channel blockers; design; extracellular; inflammatory pain; insight; mutant; novel; novel therapeutics; patch clamp; purinoceptor P2X5; receptor; receptor function; small molecule; transmission process

Tlie long term goal of this study is to elucidate tfie molecular mechanisms underlying P2X receptor functions by combining structural and functional approaches. P2X receptors are trimeric ATP-gated ion channels that are widely distributed throughout the human body. Activation of these receptors causes cation influx that evokes action potentials or triggers calcium mediated signaling, important functions in signal transmission, inflammation, and pain sensation. While the first crystal structure in its closed state provides a number of novel insights into receptor architecture, mechanisms of P2X receptor functions are largely unknown. To determine the cation selection mechanism and the structural changes during gating, two specific aims are designed as follows; 1) to identify the ion selection machinery using patch clamp recording techniques, and 2) to localize ion binding sites and determine the crystal structure in the open state using X-ray crystallography. Completion of these studies is expected to provide the first compelling mechanisms and structural basis for the cation selectivity, which may in turn lead to the design of novel pharmacological agents targeting P2X receptors.

这项研究的长期目标是阐明P2X受体函数的基于分子机制 通过结合结构和功能方法。 P2X受体是三聚体ATP门控离子通道 广泛分布在整个人体中。这些受体的激活导致阳离子流入 唤起动作电位或触发钙介导的信号传导，信号传递中的重要功能， 炎症和疼痛感。虽然其封闭状态下的第一个晶体结构提供了许多 对受体结构的新见解，P2X受体功能的机制在很大程度上未知。到 确定阳离子选择机制和门控过程中的结构变化，两个具体的目的是 设计如下； 1）使用补丁夹记录技术识别离子选择机械，然后 2）要定位离子结合位点，并使用X射线确定开放状态的晶体结构 晶体学。这些研究的完成有望提供第一个引人入胜的机制，并且 阳离子选择性的结构基础，这可能导致新的药理设计 靶向P2X受体的药物。