8EQ4 の概要
| エントリーDOI | 10.2210/pdb8eq4/pdb |
| EMDBエントリー | 28535 |
| 分子名称 | Proton-activated chloride channel, 2-acetamido-2-deoxy-beta-D-glucopyranose, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate (3 entities in total) |
| 機能のキーワード | pac, tmem206, asor, paorac, ion channels, chloride channel, membrane protein |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 3 |
| 化学式量合計 | 125170.34 |
| 構造登録者 | |
| 主引用文献 | Mihaljevic, L.,Ruan, Z.,Osei-Owusu, J.,Lu, W.,Qiu, Z. Inhibition of the proton-activated chloride channel PAC by PIP 2. Elife, 12:-, 2023 Cited by PubMed Abstract: Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by (). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP-binding. Structural and electrophysiological analyses suggest that PIP inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel. PubMed: 36633397DOI: 10.7554/eLife.83935 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.71 Å) |
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