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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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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 |
format | Online Article Text |
id | pubmed-5378477 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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