Voltage-activated potassium (Kv) channels open upon membrane depolarization and proceed to spontaneously inactivate. Inactivation controls neuronal firing rates and serves as a form of short-term memory, and is implicated in various human neurological disorders. Here, we use high-resolution cryo-electron microscopy and computer simulations to determine one of the molecular mechanisms underlying this physiologically crucial process. Structures of the activated Shaker Kv channel and of its W434F mutant in lipid bilayers demonstrate that C-type inactivation entails the dilation of the ion selectivity filter, and the repositioning of neighboring residues known to be functionally critical. Microsecond-scale molecular dynamics trajectories confirm these changes inhibit rapid ion permeation through the channel. This long-sought breakthrough establishes how eukaryotic K⁺ channels self-regulate their functional state through the plasticity of their selectivity filters.

中文翻译：

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Shaker Kv通道的结构和缓慢C型失活的机制

电压激活的钾 (Kv) 通道在膜去极化时打开并继续自发失活。失活控制神经元放电率并作为短期记忆的一种形式，并与各种人类神经系统疾病有关。在这里，我们使用高分辨率低温电子显微镜和计算机模拟来确定这一生理关键过程的分子机制之一。激活的 Shaker Kv 通道及其在脂质双层中的 W434F 突变体的结构表明，C 型失活需要离子选择性过滤器的扩张，以及已知功能关键的相邻残基的重新定位。微秒级分子动力学轨迹证实这些变化抑制了离子通过通道的快速渗透。⁺通道通过其选择性过滤器的可塑性自我调节其功能状态。