9BPC

Cryo-EM structure of P2X3 receptor in complex with camlipixant

これはPDB形式変換不可エントリーです。

9BPC の概要

• エントリーDOI: 10.2210/pdb9bpc/pdb
• 関連するPDBエントリー: 5svj 5svk
• EMDBエントリー: 44771
• 分子名称: P2X purinoceptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, Camlipixant, ... (4 entities in total)
• 機能のキーワード: p2x3, camlipixant, cryo-em, ion channel, receptor, membrane protein
• 由来する生物種: Canis lupus (gray wolf)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 124744.76

構造登録者

Thach, T.,Subramanian, R. (登録日: 2024-05-07, 公開日: 2025-03-19)

主引用文献

Thach, T.,Dhanabalan, K.,Nandekar, P.P.,Stauffer, S.,Heisler, I.,Alvarado, S.,Snyder, J.,Subramanian, R.
Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.
J.Biol.Chem., 301:108109-108109, 2025

PubMed Abstract: ATP-activated P2X3 receptors play a pivotal role in chronic cough, affecting more than 10% of the population. Despite the challenges posed by the highly conserved structure of P2X receptors, efforts to develop selective drugs targeting P2X3 have led to the development of camlipixant, a potent, selective P2X3 antagonist. However, the mechanisms of receptor desensitization, ion permeation, and structural basis of camlipixant binding to P2X3 remain unclear. Here, we report a cryo-EM structure of camlipixant-bound P2X3, revealing a previously undiscovered selective drug-binding site in the receptor. Our findings also demonstrate that conformational changes in the upper body domain, including the turret and camlipixant-binding pocket, play a critical role: turret opening facilitates P2X3 channel closure to a radius of 0.7 Å, hindering cation transfer, whereas turret closure leads to channel opening. Structural and functional studies combined with molecular dynamics simulations provide a comprehensive understanding of camlipixant's selective inhibition of P2X3, offering a foundation for future drug development targeting this receptor.

PubMed: 39706278
DOI: 10.1016/j.jbc.2024.108109

実験手法

ELECTRON MICROSCOPY (3.44 Å)