1. Structural Biology and Molecular Biophysics
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Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

  1. Sandip Basak
  2. Nicolaus Schmandt
  3. Yvonne Gicheru
  4. Sudha Chakrapani  Is a corresponding author
  1. Case Western Reserve University, United States
  2. The University of Chicago, United States
Research Article
  • Cited 41
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Cite this article as: eLife 2017;6:e23886 doi: 10.7554/eLife.23886

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.

Article and author information

Author details

  1. Sandip Basak

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. 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.
  3. Yvonne Gicheru

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
    ORCID icon "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

  1. Baron Chanda, University of Wisconsin-Madison, United States

Publication history

  1. Received: December 5, 2016
  2. Accepted: March 4, 2017
  3. Accepted Manuscript published: March 6, 2017 (version 1)
  4. Version of Record published: April 3, 2017 (version 2)
  5. 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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