8VIC

AP-6 bound human TMEM175

これはPDB形式変換不可エントリーです。

8VIC の概要

• エントリーDOI: 10.2210/pdb8vic/pdb
• EMDBエントリー: 43257
• 分子名称: Endosomal/lysosomal potassium channel TMEM175, (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine) (2 entities in total)
• 機能のキーワード: ion channel, lysosome, potassium channel, transport 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: 111596.75

構造登録者

Oh, S.,Hite, R.K. (登録日: 2024-01-03, 公開日: 2024-08-14, 最終更新日: 2025-02-26)

主引用文献

Oh, S.,Lee, J.,Choi, H.J.,Kim, S.,Sapuru, V.,Kim, M.,Hite, R.K.
Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175.
J.Am.Chem.Soc., 146:23230-23239, 2024

PubMed Abstract: TMEM175 is a lysosomal potassium and proton channel that is associated with the development of Parkinson's disease. Advances in understanding the physiological roles of TMEM175 have been hampered by the absence of selective inhibitors, and studies involving genetic perturbations have yielded conflicting results. Here, we report the discovery and characterization of the first reported TMEM175-selective inhibitors, 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes. These inhibitors may serve as valuable tools to study the roles of TMEM175 in regulating lysosomal function and provide useful templates for future therapeutic development in Parkinson's disease.

PubMed: 39116214
DOI: 10.1021/jacs.4c05623

実験手法

ELECTRON MICROSCOPY (3.48 Å)