Insights into the channel gating of P2X receptors from structures, dynamics and small molecules
Insights into the channel gating of P2X receptors from structures, dynamics and small molecules
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DOI：
10.1038/aps.2015.127
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Jin Wang;Ye Yu
中科院分区：
文献类型：
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作者：
Jin Wang;Ye Yu
P2X受体作为ATP门控的非选择性三聚体离子通道，对Na+、K+和Ca2+具有通透性。与其他配体门控离子通道家族相比，P2X受体具有独特的门控特性和病理生理作用，是治疗神经病理性疼痛、多发性硬化、类风湿性关节炎和血栓等多种疾病的理想药物靶点。针对不同P2X亚型的几种小分子抑制剂已进入临床试验。然而，关于P2X的门控机制的许多问题仍然没有解决。P2X受体在静息态和ATP结合开放态的结构测定揭示了P2X受体门控是一个涉及多个结构域的协同变构过程，标志着P2X研究进入了原子水平的后结构时代。本文综述了P2X受体的结构与功能关系，描述了通道门控过程中变构变化的全貌，并总结了可能有助于开发以P2X受体为靶点的新型变构药物的活性位点。
P2X receptors, as ATP-gated non-selective trimeric ion channels, are permeable to Na+, K+ and Ca 2+. Comparing with other ligand-gated ion channel families, P2X receptors are distinct in their unique gating properties and pathophysiological roles, and have attracted attention as promising drug targets for a variety of diseases, such as neuropathic pain, multiple sclerosis, rheumatoid arthritis and thrombus. Several small molecule inhibitors for distinct P2X subtypes have entered into clinical trials. However, many questions regarding the gating mechanism of P2X remain unsolved. The structural determinations of P2X receptors at the resting and ATP-bound open states revealed that P2X receptor gating is a cooperative allosteric process involving multiple domains, which marks the beginning of the post-structure era of P2X research at atomic level. Here, we review the current knowledge on the structure-function relationship of P2X receptors, depict the whole picture of allosteric changes during the channel gating, and summarize the active sites that may contribute to new strategies for developing novel allosteric drugs targeting P2X receptors.