Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.
Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), 1-1, Oho, Tsukuba 305-0801, Japan.
Structure. 2021 Mar 4;29(3):203-212.e4. doi: 10.1016/j.str.2020.12.007. Epub 2021 Jan 14.
The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the pharmaceutical industry. The three-dimensional structure of the hERG channel was recently reported at 3.8-Å resolution using cryogenic electron microscopy (cryo-EM). However, the drug inhibition mechanism remains unclear because of the scarce structural information regarding the drug- and potassium-bound hERG channels. In this study, we obtained the cryo-EM density map of potassium-bound hERG channel complexed with astemizole, a well-known hERG inhibitor that increases risk of potentially fatal arrhythmia, at 3.5-Å resolution. The structure suggested that astemizole inhibits potassium conduction by binding directly below the selectivity filter. Furthermore, we propose a possible binding model of astemizole to the hERG channel and provide insights into the unusual sensitivity of hERG to several drugs.
hERG 通道是一种参与心脏复极化的电压门控钾通道。药物对 hERG 的非靶点抑制已成为制药行业的一个关键问题。最近，使用低温电子显微镜（cryo-EM）以 3.8-Å 的分辨率报道了 hERG 通道的三维结构。然而，由于关于药物结合和钾结合的 hERG 通道的结构信息很少，药物抑制机制仍不清楚。在这项研究中，我们获得了与阿替米唑结合的钾结合 hERG 通道复合物的低温电镜密度图，阿替米唑是一种众所周知的 hERG 抑制剂，可增加潜在致命性心律失常的风险，分辨率为 3.5-Å。该结构表明，阿替米唑通过直接结合在选择性过滤器下方来抑制钾传导。此外，我们提出了阿替米唑与 hERG 通道的可能结合模型，并深入了解 hERG 对几种药物的异常敏感性。
