Molecular mechanism of ATP binding and ion channel activation in P2X receptors

摘要

P2X receptors are trimeric ATP-activated ion channels permeable to Na~+, K~+ andCa~(2+). The seven P2X receptorsubtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X_4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body p-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.%P2X受体是ATP激发的离子通道，Na~+、K~+和Ca~(2+)离子可以从中渗透。这些蛋白参与系列生理过程，其中包括突触传输的调制、平滑肌的收缩、化学传递介质的分泌和免疫反应的调控。在这项研究中，作者们报告了在A丁P存在和不存在两种情况下斑马鱼P2X4受体的×一射线晶体结构。与ATP相结合的结构显示了一个以前没有被看到的主题，同时两种结构的对比表明，ATP的结合导致细胞外前庭的辐射状扩大，这会引起跨膜螺旋体像虹膜一样的扩张，从而将该离子通道打开。