Faculté de Pharmacie, Laboratoire de Biophysicochimie des Récepteurs Canaux, UMR 7199 CNRS, Conception et Application de Molécules Bioactives, Université de Strasbourg, Illkirch, France.
EMBO J. 2012 May 2;31(9):2134-43. doi: 10.1038/emboj.2012.75. Epub 2012 Mar 30.
The opening of ligand-gated ion channels in response to agonist binding is a fundamental process in biology. In ATP-gated P2X receptors, little is known about the molecular events that couple ATP binding to channel opening. In this paper, we identify structural changes of the ATP site accompanying the P2X2 receptor activation by engineering extracellular zinc bridges at putative mobile regions as revealed by normal mode analysis. We provide evidence that tightening of the ATP sites shaped like open 'jaws' induces opening of the P2X ion channel. We show that ATP binding favours jaw tightening, whereas binding of a competitive antagonist prevents gating induced by this movement. Our data reveal the inherent dynamic of the binding jaw, and provide new structural insights into the mechanism of P2X receptor activation.
配体门控离子通道在响应激动剂结合时的开启是生物学中的一个基本过程。在 ATP 门控 P2X 受体中，对于将 ATP 结合与通道开启偶联的分子事件知之甚少。在本文中，我们通过工程化设计位于推测的可移动区域的细胞外锌桥，确定了与 P2X2 受体激活相关的 ATP 结合位点的结构变化，这些可移动区域是通过正常模式分析揭示的。我们提供的证据表明，像张开的“下颚”一样的 ATP 结合位点的收紧会诱导 P2X 离子通道的开启。我们表明，ATP 结合有利于下颚收紧，而竞争性拮抗剂的结合则阻止了这种运动引起的门控。我们的数据揭示了结合下颚的固有动态，并为 P2X 受体激活的机制提供了新的结构见解。
