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-Structure paper
タイトル | Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors. |
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ジャーナル・号・ページ | Structure, Year 2024 |
掲載日 | 2024年9月18日 |
著者 | Yasuomi Miyashita / Toshio Moriya / Takafumi Kato / Masato Kawasaki / Satoshi Yasuda / Naruhiko Adachi / Kano Suzuki / Satoshi Ogasawara / Tetsuichiro Saito / Toshiya Senda / Takeshi Murata / |
PubMed 要旨 | 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 ...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. |
リンク | Structure / PubMed:39321803 |
手法 | EM (単粒子) |
解像度 | 3.18 - 3.29 Å |
構造データ | EMDB-60573: Cryo-EM Structure of inhibitor-free hERG Channel EMDB-60574: Cryo-EM Structure of astemizole-bound hERG Channel EMDB-60575: Cryo-EM Structure of E-4031-bound hERG Channel EMDB-60576: Cryo-EM Structure of pimozide-bound hERG Channel |
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