9LI2

DCA-bound state of hPAC structure

9LI2 の概要

• エントリーDOI: 10.2210/pdb9li2/pdb
• EMDBエントリー: 63110
• 分子名称: Proton-activated chloride channel, (3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID (2 entities in total)
• 機能のキーワード: hpac, dca, structual protein, 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: 135223.53

構造登録者

Zhang, H.,Chen, X. (登録日: 2025-01-13, 公開日: 2025-07-30, 最終更新日: 2025-08-06)

主引用文献

Zhang, H.,Zhao, Z.,Chen, X.,Ma, Q.,Zhen, W.,Xu, Q.,Wang, Y.,He, B.,Huang, Y.,Xu, P.,Xu, H.,Lu, Z.,Su, N.,Yang, F.
Discovery and structural basis of endogenous and exogenous inhibitors of the proton-activated-chloride channel.
Cell Rep, 44:115998-115998, 2025

PubMed Abstract: The proton-activated chloride (PAC) channel is a broadly expressed chloride channel that senses extracellular acidification, regulates endosomal acidification, and participates in many processes, including acid-induced cell death and cancer cell migration. However, the lack of specific modulators has limited our understanding of its function and therapeutic potential. Here, we discovered that endogenous cholesterol (CHL) partially inhibits PAC channel activation. Moreover, we identified a series of CHL analogs and structurally related dyes as full antagonists of the PAC channel, with deoxycholic acid (DCA) and Evans blue (EB) as their representative compounds. By combining cryo-electron microscopy (cryo-EM) and patch-clamp recordings, we revealed the distinct binding and inhibition mechanisms of DCA and EB on this channel. Moreover, in malignant osteosarcoma cells, where PAC channel expression is upregulated, EB inhibited the migration and invasion of these cells. Therefore, we identified DCA and EB as pharmacological tools for the PAC channel, which forms a basis for future drug discovery targeting this channel.

PubMed: 40664207
DOI: 10.1016/j.celrep.2025.115998

実験手法

ELECTRON MICROSCOPY (3.72 Å)