5SVP

Anomalous sulfur signal reveals the position of agonist 2-methylthio-ATP bound to the ATP-gated human P2X3 ion channel in the desensitized state

5SVP の概要

• エントリーDOI: 10.2210/pdb5svp/pdb
• 関連するPDBエントリー: 5SVJ 5SVK 5SVL 5SVM 5SVQ 5SVR 5SVS 5SVT
• 分子名称: P2X purinoceptor 3, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-(methylsulfanyl)adenosine 5'-(tetrahydrogen triphosphate), ... (7 entities in total)
• 機能のキーワード: ion channel, desensitized state, anomalous signal, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84127.62

構造登録者

Mansoor, S.E.,Lu, W.,Oosterheert, W.,Shekhar, M.,Tajkhorshid, E.,Gouaux, E. (登録日: 2016-08-07, 公開日: 2016-09-28, 最終更新日: 2024-11-20)

主引用文献

Mansoor, S.E.,Lu, W.,Oosterheert, W.,Shekhar, M.,Tajkhorshid, E.,Gouaux, E.
X-ray structures define human P2X3 receptor gating cycle and antagonist action.
Nature, 538:66-71, 2016

PubMed Abstract: P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.

PubMed: 27626375
DOI: 10.1038/nature19367

実験手法

X-RAY DIFFRACTION (3.298 Å)