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- EMDB-65304: The TUG-891-bound structure of TMEM175 -

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Basic information

Entry
Database: EMDB / ID: EMD-65304
TitleThe TUG-891-bound structure of TMEM175
Map data
Sample
  • Complex: DCY1020-bound structure of TMEM175
    • Protein or peptide: Endosomal/lysosomal proton channel TMEM175
  • Ligand: 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid
  • Ligand: CHOLESTEROL
  • Ligand: POTASSIUM ION
  • Ligand: water
KeywordsTMEM175 / cro-EM / TUG-891 / Parkinson / lysosome / MEMBRANE PROTEIN
Function / homology
Function and homology information


lysosomal lumen pH elevation / phagosome-lysosome fusion / regulation of lysosomal lumen pH / potassium ion leak channel activity / proton channel activity / arachidonate binding / potassium channel activity / potassium ion transmembrane transport / proton transmembrane transport / neuron cellular homeostasis ...lysosomal lumen pH elevation / phagosome-lysosome fusion / regulation of lysosomal lumen pH / potassium ion leak channel activity / proton channel activity / arachidonate binding / potassium channel activity / potassium ion transmembrane transport / proton transmembrane transport / neuron cellular homeostasis / lysosome / endosome membrane / endosome / lysosomal membrane
Similarity search - Function
Endosomal/lysomomal potassium channel TMEM175 / Endosomal/lysosomal potassium channel TMEM175
Similarity search - Domain/homology
Endosomal/lysosomal proton channel TMEM175
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsZhu X / Liu H / Yin W
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Neuron / Year: 2025
Title: Structural insights into the activation of TMEM175 by small molecule.
Authors: Xuewu Zhu / Meixuan Ping / Heng Liu / Ting Yu / Zhongwen Jiang / Zhenhua Liu / Chanjing Li / Xinjiao Hou / Qinyu Chu / Shuyao Li / Caiwen Mao / Ting Luo / Chunlan Kang / Feng Wang / Chuanyan ...Authors: Xuewu Zhu / Meixuan Ping / Heng Liu / Ting Yu / Zhongwen Jiang / Zhenhua Liu / Chanjing Li / Xinjiao Hou / Qinyu Chu / Shuyao Li / Caiwen Mao / Ting Luo / Chunlan Kang / Feng Wang / Chuanyan Yang / Meiqin Tang / Zhidong Jiang / Zhaobing Gao / Hong Liu / H Eric Xu / Beisha Tang / Xi Cheng / Wanchao Yin / Yu Zhou / Ping Li /
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 ...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.
History
DepositionJul 9, 2025-
Header (metadata) releaseSep 17, 2025-
Map releaseSep 17, 2025-
UpdateSep 17, 2025-
Current statusSep 17, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65304.png

Downloads & links

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Map

FileDownload / File: emd_65304.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.36
Minimum - Maximum-1.7734212 - 2.93888
Average (Standard dev.)0.003983471 (±0.09019502)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65304_msk_1.map
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Half map: #1

Fileemd_65304_half_map_1.map
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Half map: #2

Fileemd_65304_half_map_2.map
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Sample components

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Entire : DCY1020-bound structure of TMEM175

EntireName: DCY1020-bound structure of TMEM175
Components
  • Complex: DCY1020-bound structure of TMEM175
    • Protein or peptide: Endosomal/lysosomal proton channel TMEM175
  • Ligand: 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid
  • Ligand: CHOLESTEROL
  • Ligand: POTASSIUM ION
  • Ligand: water

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Supramolecule #1: DCY1020-bound structure of TMEM175

SupramoleculeName: DCY1020-bound structure of TMEM175 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Endosomal/lysosomal proton channel TMEM175

MacromoleculeName: Endosomal/lysosomal proton channel TMEM175 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.667219 KDa
Recombinant expressionOrganism: Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)
SequenceString: MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVT VAWAAHTRLF QVVGKTDDTL ALLNLACMMT ITFLPYTFSL MVTFPDVPLG IFLFCVCVIA IGVVQALIVG Y AFHFPHLL ...String:
MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVT VAWAAHTRLF QVVGKTDDTL ALLNLACMMT ITFLPYTFSL MVTFPDVPLG IFLFCVCVIA IGVVQALIVG Y AFHFPHLL SPQIQRSAHR ALYRRHVLGI VLQGPALCFA AAIFSLFFVP LSYLLMVTVI LLPYVSKVTG WCRDRLLGHR EP SAHPVEV FSFDLHEPLS KERVEAFSDG VYAIVATLLI LDICEDNVPD PKDVKERFSG SLVAALSATG PRFLAYFGSF ATV GLLWFA HHSLFLHVRK ATRAMGLLNT LSLAFVGGLP LAYQQTSAFA RQPRDELERV RVSCTIIFLA SIFQLAMWTT ALLH QAETL QPSVWFGGRE HVLMFAKLAL YPCASLLAFA STCLLSRFSV GIFHLMQIAV PCAFLLLRLL VGLALATLRV LRGLA RPEH PPPAPTGQDD PQSQLLPAPC

UniProtKB: Endosomal/lysosomal proton channel TMEM175

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Macromolecule #2: 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}prop...

MacromoleculeName: 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid
type: ligand / ID: 2 / Number of copies: 2 / Formula: YN9
Molecular weightTheoretical: 364.409 Da
Chemical component information

ChemComp-YN9:
3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 7 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 40 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 1.38 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6wc9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 98355
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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