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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...
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Ion channels are specialized proteins on the plasma membrane that allow charged ions to pass down their electrochemical gradient. Their main function is to maintain the membrane potential which is critical for cell viability. These channels are either gated or non-gated and can transport more than a thousand ions within milliseconds for the cellular event to occur.
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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.
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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
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Lateral Fenestrations in K(+)-Channels Explored Using Molecular Dynamics Simulations.

Christian Jorgensen1, Leonardo Darré1, Victoria Oakes1

  • 1Department of Chemistry, King's College London , Britannia House, 7 Trinity Street, London SE1 1DB, U.K.

Molecular Pharmaceutics
|May 14, 2016
PubMed
Summary

Researchers investigated transmembrane fenestrations in potassium channels as drug entry points. TWIK-1 channels show open fenestrations, suggesting druggability, unlike Kv1.2 and Kir3.2 channels.

Keywords:
cavitiesdruggabilityion channelstunnels

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Area of Science:

  • Biophysics
  • Computational Biology
  • Pharmacology

Background:

  • Potassium channels are crucial drug targets due to their physiological and pathological roles.
  • Understanding drug access to binding sites is key for rational drug design.
  • The role of transmembrane fenestrations in potassium channel drug accessibility remains largely unexplored.

Purpose of the Study:

  • To investigate the existence, structure, and dynamics of transmembrane fenestrations in potassium channels.
  • To assess the potential of these fenestrations as drug entry pathways.
  • To evaluate the druggability of potassium channels via fenestrations.

Main Methods:

  • Molecular dynamics simulations of Kv1.2, GIRK2 (Kir3.2), and TWIK-1 (K2P1.1) potassium channels.
  • Analysis of fenestration structure, bottleneck radius, and conformational dynamics.
  • Druggability scoring function analysis of fenestration regions.

Main Results:

  • Identified four main lateral fenestrations with bottleneck radii of 0.9-2.4 Å across the studied channels.
  • Kv1.2 and Kir3.2 fenestrations were found to be too narrow for drug passage.
  • TWIK-1 channels exhibited dynamic fenestrations, with lipid molecules entering, suggesting potential druggability.
  • Kv and Kir channels showed limited druggability due to steric constraints, while K2P channels, like TWIK-1, showed promise.

Conclusions:

  • TWIK-1 and potentially other K2P channels possess druggable fenestrations, offering novel therapeutic avenues.
  • Kv1.2 and Kir3.2 channels are likely not druggable via fenestrations due to their constricted nature.
  • Detailed atomistic insights into TWIK-1 fenestrations highlight specific residues involved in aperture dynamics and membrane interactions.