Molecular mechanism of ATP binding and ion channel activation in P2X receptors.
Molecular mechanism of ATP binding and ion channel activation in P2X receptors.
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DOI：
10.1038/nature11010
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发表时间：
2012-05-10
期刊：
影响因子：
64.8
通讯作者：
Gouaux, Eric
中科院分区：
文献类型：
--
作者：
Hattori, Motoyuki;Gouaux, Eric
P2X受体是三聚体ATP激活的离子通道，可渗透Na+、K+和Ca+2。七种P2X受体亚型涉及生理过程，包括突触传递的调节、平滑肌的收缩、化学递质的分泌和免疫反应的调节。尽管P2X受体在细胞生理学中的重要性，但ATP结合位点的三维组成、ATP依赖性离子通道门控的结构机制和开放离子通道孔的结构尚不清楚。在这里，我们报告的晶体结构的斑马鱼P2X4受体与ATP和载脂蛋白受体的新结构的复合物。激动剂结合的结构揭示了一个以前看不见的ATP结合基序和一个开放的离子通道孔。ATP结合诱导核苷酸结合口袋的裂缝闭合、下体β折叠的弯曲和细胞外前庭的径向扩张。细胞外前庭的结构加宽通过跨膜螺旋的虹膜样扩张直接与离子通道孔的开口耦合。ATP结合位点和离子通道孔的结构描绘，以及与离子通道门控相关的构象变化，将刺激新的药理学试剂的开发。
P2X receptors are trimeric ATP-activated ion channels permeable to Na+, K+ and Ca+2. The seven P2X receptor subtypes 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 P2X4 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 β-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.
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