Department of Developmental Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan; 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. 2024 Nov 7;32(11):1926-1935.e3. doi: 10.1016/j.str.2024.08.021. Epub 2024 Sep 24.
During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.
在药物发现过程中，排除具有毒性作用的化合物至关重要。人 Ether-à-go-go 相关基因（hERG）通道对于维持心脏复极非常重要，并且由于其在药物诱导的心律失常中的作用，是药物安全性评估的关键靶点。hERG 通道的抑制可导致严重的心脏问题，包括尖端扭转型室性心动过速。了解 hERG 抑制机制对于避免这些毒性至关重要。几项结构研究阐明了抑制剂与 hERG 之间的相互作用。然而，到目前为止，取向和分辨率问题限制了详细的了解。在这里，我们使用皂素来分析 hERG 的无配体状态，这解决了取向问题并提高了分辨率。我们确定了 hERG 与阿替洛尔结合的结构，在孔道中显示出清晰的图谱。使用这种策略，我们还分析了 E-4031 和匹莫齐特的结合模式。这些对抑制剂与 hERG 相互作用的深入了解可能有助于更安全的药物设计并增强心脏安全性。
