Structural insights into the allosteric inhibition of P2X4 receptors.
Structural insights into the allosteric inhibition of P2X4 receptors.
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DOI：
10.1038/s41467-023-42164-y
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发表时间：
2023-10-13
影响因子：
16.6
通讯作者：
Hattori, Motoyuki
中科院分区：
文献类型：
--
作者：
Shen, Cheng;Zhang, Yuqing;Cui, Wenwen;Zhao, Yimeng;Sheng, Danqi;Teng, Xinyu;Shao, Miaoqing;Ichikawa, Muneyoshi;Wang, Jin;Hattori, Motoyuki
P2 X受体是ATP激活的阳离子通道，P2 X4亚型在免疫系统和中枢神经系统中发挥重要作用，特别是在神经病理性疼痛中。因此，P2 X4受体作为潜在的药物靶点越来越受到关注。在这里，我们报告了斑马鱼P2 X4受体与两种P2 X4亚型特异性拮抗剂BX 430和BAY-1797复合的冷冻电镜结构。两种拮抗剂结合到位于胞外结构域顶部亚基界面处的相同变构位点。通过电生理学进行的基于结构的突变分析确定了斑马鱼和人P2 X4受体变构抑制的重要残基。结构比较揭示了结合口袋的配体依赖性结构重排以稳定变构调节剂的结合，这反过来将防止与通道激活相关的细胞外结构域的结构变化。此外，与先前报道的其他亚型的P2 X结构的比较提供了亚型特异性变构抑制的机制见解。Cryo-EM结构揭示了化合物如何结合并抑制参与神经性疼痛的P2 X4受体，这可能有助于设计靶向P2 X4受体的药物。
P2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition. Cryo-EM structures revealed how chemical compounds bind to and inhibit P2X4 receptors involved in neuropathic pain, potentially facilitating the design of drugs targeting P2X4 receptors.
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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：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1016/j.jbc.2021.100655
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chen PF;Ma XF;Sun LF;Tian Y;Fan YZ;Li P;Xiao Z;Zhu MX;Guo CR;Li C;Yu Y;Wang J
通讯作者：
Wang J
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.8
作者：
BRAKE, AJ;WAGENBACH, MJ;JULIUS, D
通讯作者：
JULIUS, D