1. Structural Biology and Molecular Biophysics
  2. Neuroscience
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Structural basis for subtype-specific inhibition of the P2X7 receptor

  1. Akira Karasawa
  2. Toshimitsu Kawate  Is a corresponding author
  1. Cornell University, United States
Research Article
  • Cited 120
  • Views 6,106
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Cite this article as: eLife 2016;5:e22153 doi: 10.7554/eLife.22153

Abstract

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

Article and author information

Author details

  1. Akira Karasawa

    Department of Molecular Medicine, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Toshimitsu Kawate

    Department of Molecular Medicine, Cornell University, Ithaca, United States
    For correspondence
    tk499@cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5005-2031

Funding

National Institutes of Health (NS072869)

  • Toshimitsu Kawate

National Institutes of Health (GM114379)

  • Toshimitsu Kawate

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Publication history

  1. Received: October 6, 2016
  2. Accepted: December 8, 2016
  3. Accepted Manuscript published: December 9, 2016 (version 1)
  4. Version of Record published: December 21, 2016 (version 2)
  5. Version of Record updated: September 14, 2017 (version 3)

Copyright

© 2016, Karasawa & Kawate

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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