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

本研究的长期目标是阐明P2X受体功能的分子机制。 通过将结构方法和功能方法相结合。P2X受体是三聚体ATP门控离子通道， 广泛分布于人体各处。这些受体的激活会导致阳离子内流 激活动作电位或触发钙介导的信号传递，在信号传递中发挥重要作用， 发炎和痛感。虽然处于关闭状态的第一晶体结构提供了多个 对受体结构的新见解，P2X受体功能的机制在很大程度上是未知的。至 确定阳离子选择机制和门控过程中的结构变化，有两个具体的目标 设计如下：1)使用膜片钳记录技术识别离子选择机制，以及 2)利用X-射线对离子结合部位进行定位，并在开态下测定晶体结构 结晶学。预计完成这些研究将提供第一批令人信服的机制 阳离子选择性的结构基础，这反过来可能导致设计新的药理 以P2X受体为靶点的药物。

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.