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.

中文翻译：

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改进的高分辨率冷冻电镜结构揭示了 hERG 通道抑制剂的结合模式


在药物发现过程中，排除具有毒性作用的化合物至关重要。人类 ether-à-go-go-related gene （hERG） 通道对于维持心脏复极化至关重要，并且由于其在药物诱导的心律失常中的作用，它是药物安全性评估的关键靶标。hERG 通道的抑制会导致严重的心脏问题，包括尖端扭转型心动过速。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，方向和解决问题限制了详细的见解。在这里，我们使用洋地黄皂苷分析了 hERG 的 apo 状态，解决了方向问题并提高了分辨率。我们确定了与阿司咪唑结合的 hERG 的结构，在孔途径中显示了清晰的图谱。使用这种策略，我们还分析了 E-4031 和 pimozide 的结合模式。这些关于抑制剂与 hERG 相互作用的见解可能有助于更安全的药物设计并提高心脏安全性。