The human ether-a-go-go-related gene (hERG) encodes the voltage gated potassium channel (KCNH2 or Kv11.1, commonly known as hERG). This channel plays a pivotal role in the stability of phase 3 repolarization of the cardiac action potential. Although a high-resolution cryo-EM structure is available for its depolarized (open) state, the structure surprisingly did not feature many functionally important interactions established by previous biochemical and electrophysiology experiments. Using Molecular Dynamics Flexible Fitting (MDFF), we refined the structure and recovered the missing functionally relevant salt bridges in hERG in its depolarized state. We also performed electrophysiology experiments to confirm the functional relevance of a novel salt bridge predicted by our refinement protocol. Our work shows how refinement of a high-resolution cryo-EM structure helps to bridge the existing gap between the structure and function in the voltage-sensing domain (VSD) of hERG.

中文翻译：

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hERG 的冷冻电镜结构的改进：桥接结构和功能

人类 ether-a-go-go 相关基因 (hERG) 编码电压门控钾通道 (KCNH2 或 Kv11.1，通常称为 hERG)。该通道在心脏动作电位 3 期复极化的稳定性中起关键作用。尽管高分辨率低温 EM 结构可用于其去极化（开放）状态，但令人惊讶的是，该结构并没有具有许多由先前的生化和电生理学实验建立的功能上重要的相互作用。使用分子动力学柔性拟合 (MDFF)，我们改进了结构并在去极化状态下恢复了 hERG 中缺失的功能相关盐桥。我们还进行了电生理学实验，以确认我们的改进方案预测的新型盐桥的功能相关性。