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TitleImproved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors.
Journal, issue, pagesStructure, Vol. 32, Issue 11, Page 1926-11935.e3, Year 2024
Publish dateNov 7, 2024
AuthorsYasuomi Miyashita / Toshio Moriya / Takafumi Kato / Masato Kawasaki / Satoshi Yasuda / Naruhiko Adachi / Kano Suzuki / Satoshi Ogasawara / Tetsuichiro Saito / Toshiya Senda / Takeshi Murata /
PubMed AbstractDuring 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.
External linksStructure / PubMed:39321803
MethodsEM (single particle)
Resolution3.18 - 3.29 Å
Structure data

60573

8zyn

EMDB-60573, PDB-8zyn:
Cryo-EM Structure of inhibitor-free hERG Channel
Method: EM (single particle) / Resolution: 3.27 Å

60574

8zyo

EMDB-60574, PDB-8zyo:
Cryo-EM Structure of astemizole-bound hERG Channel
Method: EM (single particle) / Resolution: 3.29 Å

60575

8zyp

EMDB-60575, PDB-8zyp:
Cryo-EM Structure of E-4031-bound hERG Channel
Method: EM (single particle) / Resolution: 3.19 Å

60576

8zyq

EMDB-60576, PDB-8zyq:
Cryo-EM Structure of pimozide-bound hERG Channel
Method: EM (single particle) / Resolution: 3.18 Å

Chemicals

ChemComp-XB7:
1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine

PDB-1l2j:
Human Estrogen Receptor beta Ligand-binding Domain in Complex with (R,R)-5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol

ChemComp-1II:
3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / drug toxicity / potassium ion / hERG / cryo-EM / MEMBRANE PROTEIN

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