8ZYO

Cryo-EM Structure of astemizole-bound hERG Channel

Summary for 8ZYO

• Entry DOI: 10.2210/pdb8zyo/pdb
• EMDB information: 60574
• Descriptor: Potassium voltage-gated channel subfamily H member 2, 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine (2 entities in total)
• Functional Keywords: drug toxicity, potassium ion, herg, cryo-em, membrane protein, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 367626.91

Authors

Miyashita, Y.,Moriya, T.,Kato, T.,Kawasaki, M.,Yasuda, Y.,Adachi, N.,Suzuki, K.,Ogasawara, S.,Saito, T.,Senda, T.,Murata, T. (deposition date: 2024-06-18, release date: 2024-09-18, Last modification date: 2024-10-09)

Primary citation

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, 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

Experimental method

ELECTRON MICROSCOPY (3.29 Å)