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Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel
P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638823/ https://www.ncbi.nlm.nih.gov/pubmed/29026074 http://dx.doi.org/10.1038/s41467-017-00887-9 |
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author | Kasuya, Go Yamaura, Toshiaki Ma, Xiao-Bo Nakamura, Ryoki Takemoto, Mizuki Nagumo, Hiromitsu Tanaka, Eiichi Dohmae, Naoshi Nakane, Takanori Yu, Ye Ishitani, Ryuichiro Matsuzaki, Osamu Hattori, Motoyuki Nureki, Osamu |
author_facet | Kasuya, Go Yamaura, Toshiaki Ma, Xiao-Bo Nakamura, Ryoki Takemoto, Mizuki Nagumo, Hiromitsu Tanaka, Eiichi Dohmae, Naoshi Nakane, Takanori Yu, Ye Ishitani, Ryuichiro Matsuzaki, Osamu Hattori, Motoyuki Nureki, Osamu |
author_sort | Kasuya, Go |
collection | PubMed |
description | P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked to various diseases, such as rheumatoid arthritis and hypertension. Despite the availability of crystal structures of P2X receptors, the mechanism of competitive antagonist action for P2X receptors remains controversial. Here, we determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. A structure-based computational analysis furnishes mechanistic insights into the TNP-ATP-dependent inhibition. Our work provides structural insights into the functional mechanism of the P2X competitive antagonist. |
format | Online Article Text |
id | pubmed-5638823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56388232017-10-17 Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel Kasuya, Go Yamaura, Toshiaki Ma, Xiao-Bo Nakamura, Ryoki Takemoto, Mizuki Nagumo, Hiromitsu Tanaka, Eiichi Dohmae, Naoshi Nakane, Takanori Yu, Ye Ishitani, Ryuichiro Matsuzaki, Osamu Hattori, Motoyuki Nureki, Osamu Nat Commun Article P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked to various diseases, such as rheumatoid arthritis and hypertension. Despite the availability of crystal structures of P2X receptors, the mechanism of competitive antagonist action for P2X receptors remains controversial. Here, we determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. A structure-based computational analysis furnishes mechanistic insights into the TNP-ATP-dependent inhibition. Our work provides structural insights into the functional mechanism of the P2X competitive antagonist. Nature Publishing Group UK 2017-10-12 /pmc/articles/PMC5638823/ /pubmed/29026074 http://dx.doi.org/10.1038/s41467-017-00887-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kasuya, Go Yamaura, Toshiaki Ma, Xiao-Bo Nakamura, Ryoki Takemoto, Mizuki Nagumo, Hiromitsu Tanaka, Eiichi Dohmae, Naoshi Nakane, Takanori Yu, Ye Ishitani, Ryuichiro Matsuzaki, Osamu Hattori, Motoyuki Nureki, Osamu Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title | Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title_full | Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title_fullStr | Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title_full_unstemmed | Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title_short | Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel |
title_sort | structural insights into the competitive inhibition of the atp-gated p2x receptor channel |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638823/ https://www.ncbi.nlm.nih.gov/pubmed/29026074 http://dx.doi.org/10.1038/s41467-017-00887-9 |
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