5U2H

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

Summary for 5U2H

• Entry DOI: 10.2210/pdb5u2h/pdb
• Related: 5U1L 5U1U 5U1V 5U1W 5U1X 5U1Y
• Descriptor: 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)
• Functional Keywords: membrane protein: atp-gated ion channel: agonist and allosteric antagonist bound: closed state, membrane protein
• Biological source: Ailuropoda melanoleuca (Giant panda)
• Total number of polymer chains: 2
• Total formula weight: 79640.40

Authors

Karasawa, A.,Kawate, T. (deposition date: 2016-11-30, release date: 2017-01-04, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.903 Å)