Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel

Go Kasuya, Toshiaki Yamaura, Xiao-Bo Ma, Ryoki Nakamura, Mizuki Takemoto, Hiromitsu Nagumo, Eiichi Tanaka, Naoshi Dohmae, Takanori Nakane, Ye Yu, Ryuichiro Ishitani, Osamu Matsuzaki (), Motoyuki Hattori () and Osamu Nureki ()
Additional contact information
Go Kasuya: The University of Tokyo
Toshiaki Yamaura: Asahi Kasei Pharma Corporation
Xiao-Bo Ma: Institute of Medical Sciences, School of Medicine, Shanghai Jiao Tong University
Ryoki Nakamura: The University of Tokyo
Mizuki Takemoto: The University of Tokyo
Hiromitsu Nagumo: Asahi Kasei Pharma Corporation
Eiichi Tanaka: Asahi Kasei Pharma Corporation
Naoshi Dohmae: Global Research Cluster, RIKEN
Takanori Nakane: The University of Tokyo
Ye Yu: Institute of Medical Sciences, School of Medicine, Shanghai Jiao Tong University
Ryuichiro Ishitani: The University of Tokyo
Osamu Matsuzaki: Asahi Kasei Pharma Corporation
Motoyuki Hattori: Fudan University
Osamu Nureki: The University of Tokyo

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00887-9

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