Related Experiment Video

Updated: Jun 12, 2025

Do's and Don'ts of Cryo-electron Microscopy: A Primer on Sample Preparation and High Quality Data Collection for Macromolecular 3D Reconstruction
09:25

Do's and Don'ts of Cryo-electron Microscopy: A Primer on Sample Preparation and High Quality Data Collection for Macromolecular 3D Reconstruction

Published on: January 9, 2015

46.1K

Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors

Yasuomi Miyashita1, Toshio Moriya2, Takafumi Kato3

  • 1Department of Developmental Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan; Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.

Structure (London, England : 1993)
|September 25, 2024
PubMed

Insights

This study reveals new structures of the hERG channel, clarifying how drugs bind and potentially cause cardiac issues. These findings will help design safer medications by avoiding hERG channel inhibition.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Structural Biology

Background:

  • The human ether-à-go-go-related gene (hERG) channel is critical for cardiac repolarization.
  • hERG channel inhibition by drugs can cause dangerous arrhythmias like Torsades de Pointes.
  • Previous structural studies of hERG inhibitors had limitations in resolution and orientation.

Purpose of the Study:

  • To resolve orientation and resolution issues in hERG channel structural analysis.
  • To elucidate the binding mechanisms of hERG channel inhibitors.
  • To provide insights for safer drug design and improved cardiac safety.

Main Methods:

  • Utilized digitonin for analyzing the apo state of the hERG channel.
  • Determined the structure of hERG bound to astemizole.
  • Analyzed binding modes of E-4031 and pimozide using the developed strategy.

Main Results:

  • Digitonin improved hERG channel orientation and resolution.
  • A clear map of astemizole binding within the hERG channel pore was obtained.
  • Binding modes for E-4031 and pimozide were elucidated.

Conclusions:

  • The study provides high-resolution structures of hERG channel-inhibitor complexes.
  • Detailed insights into inhibitor interactions within the hERG channel pore were achieved.
  • This work facilitates the design of safer drugs with reduced cardiac risks.

Keywords:
cryo-EM structurehERG channelinhibitorpreferred orientationtoxicity

More Related Videos

Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps09:30

Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps

Published on: July 19, 2024

1.2K
Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO13:02

Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO

Published on: December 28, 2019

7.4K

Related Concept Videos

Cryo-electron Microscopy01:28

Cryo-electron Microscopy

Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...
3.3K
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.2K
Ligand-gated Ion Channels01:19

Ligand-gated Ion Channels

Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
12.3K
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
542