9VSR

The DCY1040 and TUG-891-bound structure of TMEM175

This is a non-PDB format compatible entry.

Summary for 9VSR

• Entry DOI: 10.2210/pdb9vsr/pdb
• EMDB information: 65305
• Descriptor: Endosomal/lysosomal proton channel TMEM175, 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid, CHOLESTEROL, ... (6 entities in total)
• Functional Keywords: tmem175, cro-em, agonist, parkinson, lysosome, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 113818.87

Authors

Zhu, X.,Liu, H.,Yin, W. (deposition date: 2025-07-09, release date: 2025-09-17, Last modification date: 2025-11-19)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.92 Å)