小柯机器人

英国牛津大学Elisabeth P. Carpenter和德国马尔堡大学Niels Decher团队合作取得一项新突破。他们发现TWIK相关酸敏感钾离子（TASK）通道中较低的X门在前庭膜内捕获抑制剂。2020年4月29日，国际学术期刊《自然》在线发表了这一成果。

研究人员解析了TASK-1的X衍射晶体结构，结构显示它包含一个较低的门（研究人员将其称为“ X门”），该门是由前庭中两个交叉的C端M4跨膜螺旋相互作用形成的入口。该结构由六个残基（243VLRFMT248）组成，这是对挥发性麻醉剂、神经递质和G蛋白偶联受体反应所必须的。X门和周围区域内的突变显著影响通道开放的可能性和麻醉剂对通道的激活。与两种高亲和力抑制剂结合的TASK-1结构显示，这两种化合物都在选择性过滤器下方结合，并被X门捕获在前庭中，这解析了其极低的洗脱率。TASK通道中X门的存在解释了其生理和药理行为的许多方面，这将有利于TASK调节剂的开发和优化，以治疗心脏、肺部疾病和睡眠障碍。

据了解，TASK通道是双孔道钾（K_2P）通道家族的成员，其位于神经元、心肌细胞和血管平滑肌细胞中，它们参与心脏的调节、速率、肺动脉张力、睡眠/唤醒周期以及对挥发性麻醉剂的反应。K_2P通道调节静止的膜电位，提供背景K ⁺电流，该电流由多种生理刺激控制。与其他K_2P通道不同，TASK通道能够以高亲和力、高度选择性和非常慢的化合物洗脱速率结合抑制剂。因此，这些通道是有潜力的药物靶点，并且TASK-1抑制剂目前正处在阻塞性睡眠呼吸暂停和房颤的临床试验中。通常，钾离子通道的前庭膜在其上方有一个选择性过滤器，而闸门则在其下方有四个平行的螺旋。但是，到目前为止研究的K_2P通道都没有较低的通道。

附：英文原文

Title: A lower X-gate in TASK channels traps inhibitors within the vestibule

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

Issue&Volume: 2020-04-29

Abstract: TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family—are found in neurons1, cardiomyocytes2,3,4 and vascular smooth muscle cells5, where they are involved in the regulation of heart rate6, pulmonary artery tone5,7, sleep/wake cycles8 and responses to volatile anaesthetics8,9,10,11. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli12,13,14,15. Unlike other K2P 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 fibrillation16. 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 K2P 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 (243VLRFMT248) that are essential for responses to volatile anaesthetics10, neurotransmitters13 and G-protein-coupled receptors13. 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.

DOI: 10.1038/s41586-020-2250-8

Source: https://www.nature.com/articles/s41586-020-2250-8

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