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首页> 外文期刊>Nature >A lower X-gate in TASK channels traps inhibitors within the vestibule
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A lower X-gate in TASK channels traps inhibitors within the vestibule

机译：任务通道中的较低X门捕获前庭内的抑制器

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摘要

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an 'X-gate'-created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.
机译：TWIK相关的酸敏感钾（任务）通道 - 两个孔结构型钾（K-2P）通道家族的构件 - 在神经元（1），心肌细胞（2-4）和血管平滑肌细胞（5）中发现，在那里他们参与了心率（6），肺动脉基调（5,7），睡眠/唤醒循环（8）和对挥发性麻醉剂的反应（8-11）的调节。 K-2P通道调节静止膜电位，提供由许多生理刺激（12-15）控制的背景K +电流。与其他K-2P通道不同，任务通道能够结合具有高亲和力，特殊选择性和非常慢的复合冲洗速率的抑制剂。因此，这些通道是有吸引力的药物靶标，任务-1抑制剂目前正在临床试验中用于阻塞性睡眠呼吸暂停和心房颤动（16）。通常，钾通道具有夹层前庭，其具有上方的选择性滤波器和位于下面的四个平行螺旋的栅极;然而，到目前为止研究的K-2P频道都缺乏较低的浇口。在这里，我们介绍了任务-1的X射线晶体结构，并表明它包含一个较低的门 - 我们指定作为前庭在前庭的两个交叉的C终端M4跨膜螺旋相互作用的“X-Gate”入口。该结构由六个残基（（VLRFMT248）-V-243）形成，这对于对挥发性麻醉剂（10），神经递质（13）和G蛋白偶联受体（13）的反应是必不可少的。 X栅极和周围区域内的突变显着影响通道开放概率和通过麻醉剂的激活。任务-1与两个高亲和力抑制剂结合的结构表明，两种化合物在选择性过滤器下方结合，并被X栅极捕获在前庭中，X栅极解释了它们的异常低的冲洗速率。任务渠道中的X-Gate的存在解释了它们的生理和药理学行为的许多方面，这将有利于未来的开发和优化任务调节剂的治疗心脏，肺和睡眠障碍。X射线晶体结构钾通道任务-1揭示了X型栅极的存在，其捕获intremermany前庭中的小分子抑制剂，并从通道中解释了它们的低冲洗速率。

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  • 来源
    《Nature》 |2020年第7812期|443-447|共5页
  • 作者

    Rodstrom Karin E. J.; Kiper Aytug K.; Zhang Wei; Rinne Susanne; Pike Ashley C. W.; Goldstein Matthias; Conrad Linus J.; Delbeck Martina; Hahn Michael G.; Meier Heinrich; Platzk Magdalena; Quigley Andrew; Speedman David; Shrestha Leela; Mukhopadhyay Shubhashish M. M.; Burgess-Brown Nicola A.; Tucker Stephen J.; Mueller Thomas; Decher Niels; Carpenter Elisabeth P.;

  • 作者单位

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Marburg Inst Physiol & Pathophysiol Vegetat Physiol & Marburg Ctr Mind Brain & Behav Marburg Germany;

    Univ Oxford Struct Genom Consortium Oxford England|Chinese Acad Sci Inst Microbiol Publ Technol Serv Ctr Beijing Peoples R China|Chinese Acad Sci Inst Microbiol CAS Key Lab Pathogen Microbiol & Immunol Beijing Peoples R China;

    Univ Marburg Inst Physiol & Pathophysiol Vegetat Physiol & Marburg Ctr Mind Brain & Behav Marburg Germany;

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Marburg Inst Physiol & Pathophysiol Vegetat Physiol & Marburg Ctr Mind Brain & Behav Marburg Germany;

    Univ Oxford Dept Phys Oxford England|Univ Sheffield Dept Biomed Sci Sheffield S Yorkshire England;

    Bayer AG Res & Dev Pharmaceut Wuppertal Germany;

    Bayer AG Res & Dev Pharmaceut Wuppertal Germany;

    Bayer AG Res & Dev Pharmaceut Wuppertal Germany;

    Bayer AG Res & Dev Pharmaceut Wuppertal Germany;

    Univ Oxford Struct Genom Consortium Oxford England|Res Complex Harwell Membrane Prot Lab Harwell Berks England;

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Oxford Struct Genom Consortium Oxford England;

    Univ Oxford Dept Phys Oxford England;

    Bayer AG Res & Dev Pharmaceut Wuppertal Germany;

    Univ Marburg Inst Physiol & Pathophysiol Vegetat Physiol & Marburg Ctr Mind Brain & Behav Marburg Germany;

    Univ Oxford Struct Genom Consortium Oxford England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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