Related Experiment Video

Updated: Mar 22, 2026

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
10:20

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Published on: November 11, 2016

9.0K

New potential binding determinant for hERG channel inhibitors

P Saxena1, E-M Zangerl-Plessl1, T Linder1

  • 1Institute of Pharmacology and Toxicology, University of Vienna, Austria.

Scientific Reports
|April 13, 2016
PubMed

Insights

Researchers discovered a new binding site (F557) in the hERG1 channel

Area of Science:

  • Cardiovascular pharmacology
  • Ion channel biophysics
  • Molecular cardiology

Background:

  • Human ether-à-go-go related gene (hERG) 1 channels are critical for cardiac action potential repolarization.
  • Inhibition of hERG1 channels by drugs can cause life-threatening arrhythmias.
  • Known binding sites for hERG1 blockers are on the pore helix and S6 segment.

Purpose of the Study:

  • To investigate potential drug binding determinants on the S5 helix of hERG1 channels.
  • To identify novel sites that interact with hERG1 channel blockers.

Main Methods:

  • Two-microelectrode voltage clamp ionic current measurements.
  • Molecular modeling techniques.
  • Site-directed mutagenesis (implied by identification of specific residues).

Main Results:

  • A novel high-affinity binding determinant, phenylalanine at position 557 (F557), was identified on the S5 helix.
  • F557 demonstrated potency comparable to the known residue Y652.
  • Molecular modeling supported a direct interaction between F557 and the outer pore helix.

Conclusions:

  • The S5 helix contains a previously unrecognized aromatic binding site for hERG1 channel blockers.
  • F557 represents a significant determinant for hERG1 channel blockade.
  • Findings advance understanding of hERG1 channel-drug interactions and arrhythmia risk.

More Related Videos

High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers14:03

High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers

Published on: March 24, 2023

2.5K
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission07:16

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

Published on: August 16, 2018

14.4K

Related Concept Videos

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...
4.6K
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...
15.3K
Ligand-gated Ion Channels01:19

Ligand-gated Ion Channels

6.7K
G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
6.8K
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.6K
Drug Binding to Blood Components01:30

Drug Binding to Blood Components

When drugs enter systemic circulation, they interact with various components of the blood, including proteins such as human serum albumin (HSA), α1-acid glycoprotein (AAG), lipoproteins, globulins, and red blood cells (RBCs).
HSA is the most abundant plasma protein and is vital in drug binding. It contains distinct drug-binding sites, with different drugs exhibiting affinity for specific sites. There are three main drug-binding domains for HSA: sites I, II, and III. These domains are...
641