A shared mechanism for TNP-ATP recognition by members of the P2X receptor family.
A shared mechanism for TNP-ATP recognition by members of the P2X receptor family.
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DOI：
10.1016/j.csbj.2023.12.005
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发表时间：
2024-12
影响因子：
6
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中科院分区：
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P2X受体（P2X1-7）是非选择性阳离子通道，参与许多生理活动，如突触传递、免疫调节和心血管功能。这些受体共享一个保守的机制来感知细胞外ATP。TNP-ATP是一种ATP衍生物，作为非选择性竞争性P2X拮抗剂。了解它如何在没有激动作用的情况下占据正构位，可能有助于揭示P2X门控过程中的关键变构。然而，人们提出了具有不同构象和不同作用机制的TNP-ATP/P2X复合物（TNP-ATP/人P2X3 （hP2X3）和TNP-ATP/鸡P2X7 (ckP2X7)）。这些是否代表物种和亚型变异或实验差异尚不清楚。在这里，我们通过结合增强的构象采样、工程二硫化物键分析和共价占用，证明了P2X家族成员存在一种共同的TNP-ATP识别机制。在该模型中，TNP-ATP的极性三磷酸部分与正构位位点相互作用，而其tnp部分深深嵌入头部和背鳍（DF）界面，在这两个区域产生限制性变构，导致部分扩大但不渗透离子的孔。不同物种的多种P2X亚型，包括ckP2X7、hP2X3、大鼠P2X2 （rP2X2）和人P2X1 (hP2X1)，均获得了类似的结果。因此，TNP-ATP通过限制P2X激活所必需的头部和DF结构域的运动来使用P2X识别和调节的共同机制。这些知识适用于开发新的P2X抑制剂。
P2X receptors (P2X1–7) are non-selective cation channels involved in many physiological activities such as synaptic transmission, immunological modulation, and cardiovascular function. These receptors share a conserved mechanism to sense extracellular ATP. TNP-ATP is an ATP derivative acting as a nonselective competitive P2X antagonist. Understanding how it occupies the orthosteric site in the absence of agonism may help reveal the key allostery during P2X gating. However, TNP-ATP/P2X complexes (TNP-ATP/human P2X3 (hP2X3) and TNP-ATP/chicken P2X7 (ckP2X7)) with distinct conformations and different mechanisms of action have been proposed. Whether these represent species and subtype variations or experimental differences remains unclear. Here, we show that a common mechanism of TNP-ATP recognition exists for the P2X family members by combining enhanced conformation sampling, engineered disulfide bond analysis, and covalent occupancy. In this model, the polar triphosphate moiety of TNP-ATP interacts with the orthosteric site, while its TNP-moiety is deeply embedded in the head and dorsal fin (DF) interface, creating a restrictive allostery in these two domains that results in a partly enlarged yet ion-impermeable pore. Similar results were obtained from multiple P2X subtypes of different species, including ckP2X7, hP2X3, rat P2X2 (rP2X2), and human P2X1 (hP2X1). Thus, TNP-ATP uses a common mechanism for P2X recognition and modulation by restricting the movements of the head and DF domains which are essential for P2X activation. This knowledge is applicable to the development of new P2X inhibitors.
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影响因子：
2.7
作者：
Burnstock G
通讯作者：
Burnstock G
影响因子：
11.4
作者：
Jiang, Ruotian;Taly, Antoine;Grutter, Thomas
通讯作者：
Grutter, Thomas
影响因子：
64.8
作者：
BRAKE, AJ;WAGENBACH, MJ;JULIUS, D
通讯作者：
JULIUS, D
DOI：
10.1073/pnas.1110499108
发表时间：
2011-11-15
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
DOI：
10.1038/nri2938
发表时间：
2011-03
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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