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

Go Kasuya1, Toshiaki Yamaura2, Xiao-Bo Ma3

  • 1Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.

Nature Communications
|October 14, 2017
PubMed

Insights

Structural insights into P2X7 receptor function were revealed by determining the crystal structure of the chicken P2X7 receptor bound to the competitive antagonist TNP-ATP. This study clarifies the unique binding of TNP-ATP, offering a mechanism for P2X receptor inhibition.

Area of Science:

  • Structural Biology
  • Molecular Pharmacology
  • Immunology

Background:

  • P2X receptors are ATP-gated cation channels vital for immune and nervous system functions.
  • Dysfunction and altered expression of P2X7 receptors are implicated in diseases like rheumatoid arthritis and hypertension.
  • The precise mechanism of competitive antagonist action on P2X receptors remains incompletely understood.

Purpose of the Study:

  • To elucidate the structural basis of competitive antagonism at the P2X7 receptor.
  • To investigate the interaction between the chicken P2X7 receptor and the antagonist TNP-ATP.
  • To provide mechanistic insights into TNP-ATP-mediated inhibition.

Main Methods:

  • X-ray crystallography of the chicken P2X7 receptor in complex with TNP-ATP.
  • Structure-based computational analysis.
  • Electrophysiology measurements.

Main Results:

  • The crystal structure revealed an expanded, incompletely activated conformation of the P2X7 channel.
  • A unique binding mode of TNP-ATP to the chicken P2X7 receptor was identified, differing from human P2X3.
  • Computational analysis provided mechanistic details of TNP-ATP dependent inhibition.

Conclusions:

  • The study provides critical structural insights into the mechanism of P2X competitive antagonists.
  • The findings clarify the interaction of TNP-ATP with the P2X7 receptor, distinct from other subtypes.
  • This work advances the understanding of P2X receptor pharmacology and potential therapeutic targeting.

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