Structural basis for subtype-specific inhibition of the P2X7 receptor

Karasawa, Akira; Kawate, Toshimitsu

doi:10.7554/eLife.22153

Title: Structural basis for subtype-specific inhibition of the P2X7 receptor

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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.

Authors:

Karasawa, Akira;

Publication Date:: Fri Dec 09 00:00:00 EST 2016

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE; National Institutes of Health (NIH)

OSTI Identifier:: 1346228

Resource Type:: Journal Article

Journal Name:: eLife

Additional Journal Information:: Journal Volume: 5; Journal Issue: 2016; Journal ID: ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Karasawa, Akira, and Kawate, Toshimitsu. Structural basis for subtype-specific inhibition of the P2X7 receptor.  United States: N. p., 2016. 
        Web.  doi:10.7554/eLife.22153.

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                    Karasawa, Akira, & Kawate, Toshimitsu. Structural basis for subtype-specific inhibition of the P2X7 receptor.  United States.  https://doi.org/10.7554/eLife.22153

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                    Karasawa, Akira, and Kawate, Toshimitsu. 2016.  
        "Structural basis for subtype-specific inhibition of the P2X7 receptor".  United States.  https://doi.org/10.7554/eLife.22153.

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@article{osti_1346228,

  title        = {Structural basis for subtype-specific inhibition of the P2X7 receptor},

  author       = {Karasawa, Akira and Kawate, Toshimitsu},

  abstractNote = {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.},

  doi          = {10.7554/eLife.22153},

  url          = {https://www.osti.gov/biblio/1346228},
  journal      = {eLife},

  issn         = {2050-084X},

  number       = 2016,

  volume       = 5,

  place        = {United States},

  year         = {Fri Dec 09 00:00:00 EST 2016},

  month        = {Fri Dec 09 00:00:00 EST 2016}

}

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