Mark Cowley Lidwill Research Program, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
Nat Commun. 2024 Aug 29;15(1):7470. doi: 10.1038/s41467-024-51208-w.
The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.
生物电信号的微调是通过控制不同离子通道中离子流的门控开启和关闭速率的变化来介导的。人类 ether-a-go-go 相关基因 (HERG) 钾通道具有独特的快速失活动力学，这对其在调节心脏电活动中的作用至关重要。在这里，我们利用 HERG 失活的 K 敏感性来确定 HERG 的导电和非导电选择性过滤器结构的结构。导电状态具有典型的圆柱形选择性过滤器。非导电状态的特征是选择性过滤器缬氨酸骨架羰基翻转远离中心轴。孔螺旋上 S620 的侧链在这个过程中起着核心作用，通过在导电、非导电和过渡状态中协调不同的相互作用集。我们的模型代表了离子通道微调其活性的一种独特机制，并可以解释 HERG 独特的快速失活动力学。
