8TR7

Cryo-EM structure of the rat P2X7 receptor in complex with the allosteric antagonist A839977

8TR7 の概要

• エントリーDOI: 10.2210/pdb8tr7/pdb
• 関連するPDBエントリー: 8TR6 8TR8 8TRA 8TRB 8TRK
• EMDBエントリー: 41571 41572 41573 41575 41576 41582
• 分子名称: P2X purinoceptor 7, (1P)-1-(2,3-dichlorophenyl)-N-({2-[(pyridin-2-yl)oxy]phenyl}methyl)-1H-tetrazol-5-amine, GUANOSINE-5'-DIPHOSPHATE, ... (8 entities in total)
• 機能のキーワード: membrane protein, ion channel, ligand-gate ion channel, p2x receptor, allosteric antagonist, high-affinity agonist
• 由来する生物種: Rattus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 213575.82

構造登録者

Oken, A.C.,Ditter, I.A.,Lisi, N.E.,Krishnamurthy, I.,McCarthy, A.E.,Godsey, M.H.,Mansoor, S.E. (登録日: 2023-08-09, 公開日: 2024-10-16, 最終更新日: 2025-05-28)

主引用文献

Oken, A.C.,Ditter, I.A.,Lisi, N.E.,Krishnamurthy, I.,Godsey, M.H.,Mansoor, S.E.
P2X 7 receptors exhibit at least three modes of allosteric antagonism.
Sci Adv, 10:eado5084-eado5084, 2024

PubMed Abstract: P2X receptors are trimeric ion channels activated by adenosine triphosphate (ATP) that contribute to pathophysiological processes ranging from asthma to neuropathic pain and neurodegeneration. A number of small-molecule antagonists have been identified for these important pharmaceutical targets. However, the molecular pharmacology of P2X receptors is poorly understood because of the chemically disparate nature of antagonists and their differential actions on the seven constituent subtypes. Here, we report high-resolution cryo-electron microscopy structures of the homomeric rat P2X receptor bound to five previously known small-molecule allosteric antagonists and a sixth antagonist that we identify. Our structural, biophysical, and electrophysiological data define the molecular determinants of allosteric antagonism in this pharmacologically relevant receptor, revealing three distinct classes of antagonists that we call shallow, deep, and starfish. Starfish binders, exemplified by the previously unidentified antagonist methyl blue, represent a unique class of inhibitors with distinct functional properties that could be exploited to develop potent P2X ligands with substantial clinical impact.

PubMed: 39365862
DOI: 10.1126/sciadv.ado5084

実験手法

ELECTRON MICROSCOPY (2.53 Å)