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

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Cite this article as: eLife 2017;6:e23886 doi: 10.7554/eLife.23886

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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.

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Author details

Sandip Basak

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Nicolaus Schmandt

Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Yvonne Gicheru

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Sudha Chakrapani

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States

For correspondence
Sxc584@case.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0722-2338

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

Publication 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

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.