9VSQ

The TUG-891-bound structure of TMEM175

9VSQ の概要

• エントリーDOI: 10.2210/pdb9vsq/pdb
• EMDBエントリー: 65304
• 分子名称: Endosomal/lysosomal proton channel TMEM175, 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid, CHOLESTEROL, ... (5 entities in total)
• 機能のキーワード: tmem175, cro-em, tug-891, parkinson, lysosome, 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: 113110.25

構造登録者

Zhu, X.,Liu, H.,Yin, W. (登録日: 2025-07-09, 公開日: 2025-09-17, 最終更新日: 2025-11-19)

主引用文献

Zhu, X.,Ping, M.,Liu, H.,Yu, T.,Jiang, Z.,Liu, Z.,Li, C.,Hou, X.,Chu, Q.,Li, S.,Mao, C.,Luo, T.,Kang, C.,Wang, F.,Yang, C.,Tang, M.,Jiang, Z.,Gao, Z.,Liu, H.,Xu, H.E.,Tang, B.,Cheng, X.,Yin, W.,Zhou, Y.,Li, P.
Structural insights into the activation of TMEM175 by small molecule.
Neuron, 113:3567-, 2025

PubMed Abstract: The upregulation of transmembrane protein 175 (TMEM175) has the potential to improve Parkinson's disease (PD) by aiding in the removal of α-synuclein aggregates. Understanding the structural basis of TMEM175 agonisms is crucial for uncovering its therapeutic potential for PD. Here, we have identified the first cryo-electron microscopy (cryo-EM) structure of human TMEM175 complexes with three agonists: DCY1020, DCY1040, and TUG-891. An open state of TMEM175 is unequivocally captured, laying the groundwork for designing more effective agonists. Further investigations using surface plasmon resonance, systematic mutagenesis, whole-endolysosome patch-clamp techniques, and molecular dynamics simulations consistently revealed that DCY1020/1040 binds at the interface between two subunits, inducing an open conformation further augmented by the synergistic agonist TUG-891. Notably, these agonists facilitate the removal of pathological α-synuclein and restore functions of PD-related TMEM175 variants in neurons. Our findings provide proof of concept that drug discovery targeting TMEM175 can develop agonists capable of effectively reducing pathological α-synuclein levels in PD.

PubMed: 40865534
DOI: 10.1016/j.neuron.2025.07.029

実験手法

ELECTRON MICROSCOPY (2.74 Å)