Structural Genomics Consortium, University of Oxford, Oxford, UK.
Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, University of Marburg, Marburg, Germany.
Nature. 2020 Jun;582(7812):443-447. doi: 10.1038/s41586-020-2250-8. Epub 2020 Apr 29.
TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K) channel family-are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics. K channels regulate the resting membrane potential, providing background K currents controlled by numerous physiological stimuli. Unlike other K 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. 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 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 (VLRFMT) that are essential for responses to volatile anaesthetics, neurotransmitters and G-protein-coupled receptors. 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.
TWIK 相关酸敏感钾（TASK）通道是双孔域钾（K）通道家族的成员，存在于神经元、心肌细胞和血管平滑肌细胞中，参与调节心率、肺动脉张力、睡眠/觉醒周期和对挥发性麻醉剂的反应。K 通道调节静息膜电位，提供受多种生理刺激控制的背景 K 电流。与其他 K 通道不同，TASK 通道能够以高亲和力结合抑制剂，具有非凡的选择性和非常缓慢的化合物洗脱率。因此，这些通道是有吸引力的药物靶点，TASK-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。一般来说，钾通道具有位于膜内侧的前庭，选择性过滤器位于上方，带有四个平行螺旋的门位于下方；然而，迄今为止研究的 K 通道都缺乏下门。在这里，我们展示了 TASK-1 的 X 射线晶体结构，并表明它包含一个下门-我们将其指定为“X 门”-由前庭入口处两个交叉的 C 端 M4 跨膜螺旋相互作用形成。这个结构由六个残基（VLRFMT）组成，对于对挥发性麻醉剂、神经递质和 G 蛋白偶联受体的反应至关重要。X 门及其周围区域的突变明显影响通道的开放概率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 结构表明，两种化合物都结合在选择性过滤器下方，并且被 X 门捕获在前庭中，这解释了它们异常低的洗脱率。X 门在 TASK 通道中的存在解释了它们生理和药理学行为的许多方面，这将有助于未来开发和优化 TASK 调节剂，以治疗心脏、肺部和睡眠障碍。
