5U2H

Crystal structure of the ATP-gated P2X7 ion channel bound to ATP and allosteric antagonist A804598

5U2H の概要

• エントリーDOI: 10.2210/pdb5u2h/pdb
• 関連するPDBエントリー: 5U1L 5U1U 5U1V 5U1W 5U1X 5U1Y
• 分子名称: P2X purinoceptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, N-cyano-N'-[(1R)-1-phenylethyl]-N''-quinolin-5-ylguanidine, ... (5 entities in total)
• 機能のキーワード: membrane protein: atp-gated ion channel: agonist and allosteric antagonist bound: closed state, membrane protein
• 由来する生物種: Ailuropoda melanoleuca (Giant panda)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79640.40

構造登録者

Karasawa, A.,Kawate, T. (登録日: 2016-11-30, 公開日: 2017-01-04, 最終更新日: 2024-11-20)

主引用文献

Karasawa, A.,Kawate, T.
Structural basis for subtype-specific inhibition of the P2X7 receptor.
Elife, 5:-, 2016

PubMed 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.

PubMed: 27935479
DOI: 10.7554/eLife.22153

実験手法

X-RAY DIFFRACTION (3.903 Å)