Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel.
Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel.
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ATP 门控 P2X 受体通道竞争性抑制的结构见解。
DOI：
10.1038/s41467-017-00887-9
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发表时间：
2017-10-12
影响因子：
16.6
通讯作者：
Nureki O
中科院分区：
文献类型：
--
作者：
Kasuya G;Yamaura T;Ma XB;Nakamura R;Takemoto M;Nagumo H;Tanaka E;Dohmae N;Nakane T;Yu Y;Ishitani R;Matsuzaki O;Hattori M;Nureki O
P2X受体是由细胞外三磷酸腺苷（ATP）门控的非选择性阳离子通道，其中P2X7受体亚型在免疫系统和神经系统中起着关键作用。由基因缺失、突变和多态性变异导致的P2X7受体表达改变和功能异常，与多种疾病相关，如类风湿性关节炎和高血压。尽管已有P2X受体的晶体结构，但P2X受体竞争性拮抗剂的作用机制仍存在争议。在此，我们测定了鸡P2X7受体与竞争性P2X拮抗剂2,3,4,5 - 四氮杂 - 6 - 硝基苯 - 三磷酸腺苷（TNP - ATP）复合物的晶体结构。该结构揭示了通道处于一种扩张的、未完全激活的构象，并确定了TNP - ATP独特的识别方式，这与先前测定的人P2X3受体结构中观察到的有所不同。基于结构的计算分析为TNP - ATP依赖性抑制作用提供了机制上的见解。我们的研究为P2X竞争性拮抗剂的功能机制提供了结构层面的认识。
P2X受体是由细胞外ATP门控的非选择性阳离子通道。本文作者展示了鸡P2X7受体与其结合的竞争性拮抗剂TNP - ATP的晶体结构，并通过进一步的计算分析和电生理测量，对TNP - ATP依赖性抑制作用给出了机制上的见解。
P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked to various diseases, such as rheumatoid arthritis and hypertension. Despite the availability of crystal structures of P2X receptors, the mechanism of competitive antagonist action for P2X receptors remains controversial. Here, we determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. A structure-based computational analysis furnishes mechanistic insights into the TNP-ATP-dependent inhibition. Our work provides structural insights into the functional mechanism of the P2X competitive antagonist. P2X receptors are nonselective cation channels that are gated by extracellular ATP. Here the authors present the crystal structure of chicken P2X7 with its bound competitive antagonist TNP-ATP and give mechanistic insights into TNP-ATP dependent inhibition through further computational analysis and electrophysiology measurements.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
P2X 受体核苷酸碱基特异性的结构见解。
影响因子：
4.6
作者：
Kasuya G;Fujiwara Y;Tsukamoto H;Morinaga S;Ryu S;Touhara K;Ishitani R;Furutani Y;Hattori M;Nureki O
通讯作者：
Nureki O
影响因子：
64.8
作者：
BRAKE, AJ;WAGENBACH, MJ;JULIUS, D
通讯作者：
JULIUS, D
影响因子：
1.8
作者：
Guarnieri, Michael T.;Blagg, Brian S. J.;Zhao, Rui
通讯作者：
Zhao, Rui
影响因子：
4.7
作者：
Jindrichova, Marie;Bhattacharya, Anirban;Zemkova, Hana
通讯作者：
Zemkova, Hana