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Title: Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

Abstract

Desensitization in pentameric ligand-gated ion channels plays an important role in regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω-3 polyunsaturated fatty acid in synaptic membranes, enhances the agonist-induced transition to the desensitized state in the prokaryotic channel GLIC. We determined a 3.25 Å crystal structure of the GLIC-DHA complex in a potentially desensitized conformation. The DHA molecule is bound at the channel-periphery near the M4 helix and exerts a long-range allosteric effect on the pore across domain-interfaces. In this previously unobserved conformation, the extracellular-half of the pore-lining M2 is splayed open, reminiscent of the open conformation, while the intracellular-half is constricted, leading to a loss of both water and permeant ions. These findings, in combination with spin-labeling/EPR spectroscopic measurements in reconstituted-membranes, provide novel mechanistic details of desensitization in pentameric channels.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [1]; ORCiD logo [1]
  1. Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, United States
  2. Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHANIGMS
OSTI Identifier:
1390872
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 6; Journal Issue: 03, 2017; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Basak, Sandip, Schmandt, Nicolaus, Gicheru, Yvonne, and Chakrapani, Sudha. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. United States: N. p., 2017. Web. doi:10.7554/eLife.23886.
Basak, Sandip, Schmandt, Nicolaus, Gicheru, Yvonne, & Chakrapani, Sudha. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. United States. https://doi.org/10.7554/eLife.23886
Basak, Sandip, Schmandt, Nicolaus, Gicheru, Yvonne, and Chakrapani, Sudha. 2017. "Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel". United States. https://doi.org/10.7554/eLife.23886.
@article{osti_1390872,
title = {Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel},
author = {Basak, Sandip and Schmandt, Nicolaus and Gicheru, Yvonne and Chakrapani, Sudha},
abstractNote = {Desensitization in pentameric ligand-gated ion channels plays an important role in regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω-3 polyunsaturated fatty acid in synaptic membranes, enhances the agonist-induced transition to the desensitized state in the prokaryotic channel GLIC. We determined a 3.25 Å crystal structure of the GLIC-DHA complex in a potentially desensitized conformation. The DHA molecule is bound at the channel-periphery near the M4 helix and exerts a long-range allosteric effect on the pore across domain-interfaces. In this previously unobserved conformation, the extracellular-half of the pore-lining M2 is splayed open, reminiscent of the open conformation, while the intracellular-half is constricted, leading to a loss of both water and permeant ions. These findings, in combination with spin-labeling/EPR spectroscopic measurements in reconstituted-membranes, provide novel mechanistic details of desensitization in pentameric channels.},
doi = {10.7554/eLife.23886},
url = {https://www.osti.gov/biblio/1390872}, journal = {eLife},
issn = {2050-084X},
number = 03, 2017,
volume = 6,
place = {United States},
year = {Mon Mar 06 00:00:00 EST 2017},
month = {Mon Mar 06 00:00:00 EST 2017}
}

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