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:
-
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, United States
- 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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