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 structure of the GLIC-DHA complex in a potentially desensitized conformation. The DHA molecule is bound at the channel-periphery near M4 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.
Data availability
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Crystal Structure of membrane protein.Publicly available at the RCSB Protein Data Bank (accession no: 5J0Z).
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The GLIC pentameric Ligand-Gated Ion Channel at 2.4 A resolutionPublicly available at the RCSB Protein Data Bank (accession no: 4HFI).
Article and author information
Author details
Funding
American Heart Association (12SDG12070069)
- Sudha Chakrapani
National Institute of General Medical Sciences (R01GM108921)
- Sudha Chakrapani
National Institute of General Medical Sciences (3R01GM108921-03S1)
- Sudha Chakrapani
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Baron Chanda, University of Wisconsin-Madison, United States
Version history
- Received: December 5, 2016
- Accepted: March 4, 2017
- Accepted Manuscript published: March 6, 2017 (version 1)
- Version of Record published: April 3, 2017 (version 2)
- Version of Record updated: March 26, 2018 (version 3)
Copyright
© 2017, Basak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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