Cryo-EM Structure of the Open Human Ether-à-go-go-Related K(+) Channel hERG.
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K(+) Channel hERG.
复制标题
DOI：
10.1016/j.cell.2017.03.048
复制
发表时间：
2017-04-20
期刊：
影响因子：
64.5
通讯作者：
MacKinnon R
中科院分区：
文献类型：
--
作者：
Wang W;MacKinnon R
人的乙醚-去-去相关钾通道(HERG，Kv11.1)是一种电压依赖的通道，以其在心脏动作电位复极化中的作用而闻名。突变或药物抑制引起的HERG改变会导致长QT综合征和致死性心律失常。我们用低温电子显微镜测定了HERG的分子结构。在这种结构中，电压传感器采用去极化的构象，并且孔洞是开放的。中心腔有一个非典型的小中心体积，周围有四个深的疏水口袋，这可能解释了Herg对许多药物的异常敏感。HERG选择性过滤器的一个微妙结构特征可能与其快速失活率有关，这是HERG在心脏动作电位复极中作用的关键。对HERG通道的结构分析可能解释已知的人类通道病突变，以及为什么该通道对广泛的药物极其敏感。
The human ether-à-go-go related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure the voltage sensors adopt a depolarized conformation and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG’s unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG’s role in cardiac action potential repolarization. Structural analysis of the hERG channel may explain known human channelopathy mutations and why the channel is extremely sensitive to a wide range of drugs.