8ZYN

Cryo-EM Structure of inhibitor-free hERG Channel

8ZYN の概要

• エントリーDOI: 10.2210/pdb8zyn/pdb
• EMDBエントリー: 60573
• 分子名称: Potassium voltage-gated channel subfamily H member 2 (1 entity in total)
• 機能のキーワード: drug toxicity, potassium ion, herg, cryo-em, membrane protein, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 367168.34

構造登録者

Miyashita, Y.,Moriya, T.,Kato, T.,Kawasaki, M.,Yasuda, Y.,Adachi, N.,Suzuki, K.,Ogasawara, S.,Saito, T.,Senda, T.,Murata, T. (登録日: 2024-06-18, 公開日: 2024-09-18, 最終更新日: 2024-11-27)

主引用文献

Miyashita, Y.,Moriya, T.,Kato, T.,Kawasaki, M.,Yasuda, S.,Adachi, N.,Suzuki, K.,Ogasawara, S.,Saito, T.,Senda, T.,Murata, T.
Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors.
Structure, 32:1926-, 2024

PubMed Abstract: 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.

PubMed: 39321803
DOI: 10.1016/j.str.2024.08.021

実験手法

ELECTRON MICROSCOPY (3.27 Å)