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

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 pro...

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Autores principales: Basak, Sandip, Schmandt, Nicolaus, Gicheru, Yvonne, Chakrapani, Sudha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378477/
https://www.ncbi.nlm.nih.gov/pubmed/28262093
http://dx.doi.org/10.7554/eLife.23886
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author Basak, Sandip
Schmandt, Nicolaus
Gicheru, Yvonne
Chakrapani, Sudha
author_facet Basak, Sandip
Schmandt, Nicolaus
Gicheru, Yvonne
Chakrapani, Sudha
author_sort Basak, Sandip
collection PubMed
description 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: http://dx.doi.org/10.7554/eLife.23886.001
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spelling pubmed-53784772017-04-05 Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel Basak, Sandip Schmandt, Nicolaus Gicheru, Yvonne Chakrapani, Sudha eLife Biophysics and Structural Biology 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: http://dx.doi.org/10.7554/eLife.23886.001 eLife Sciences Publications, Ltd 2017-03-06 /pmc/articles/PMC5378477/ /pubmed/28262093 http://dx.doi.org/10.7554/eLife.23886 Text en © 2017, Basak et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biophysics and Structural Biology
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
title Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
title_full Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
title_fullStr Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
title_full_unstemmed Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
title_short Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
title_sort crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel
topic Biophysics and Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378477/
https://www.ncbi.nlm.nih.gov/pubmed/28262093
http://dx.doi.org/10.7554/eLife.23886
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