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- PDB-9vsr: The DCY1040 and TUG-891-bound structure of TMEM175 -

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Basic information

Entry
Database: PDB / ID: 9vsr
TitleThe DCY1040 and TUG-891-bound structure of TMEM175
ComponentsEndosomal/lysosomal proton channel TMEM175
KeywordsMEMBRANE PROTEIN / TMEM175 / cro-EM / agonist / Parkinson / lysosome
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
: / CHOLESTEROL / : / Chem-YN9 / Endosomal/lysosomal proton channel TMEM175
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsZhu, X. / Liu, H. / Yin, W.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 17, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Endosomal/lysosomal proton channel TMEM175
B: Endosomal/lysosomal proton channel TMEM175
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,81911
Polymers111,3342
Non-polymers2,4849
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Endosomal/lysosomal proton channel TMEM175 / Potassium channel TMEM175 / Transmembrane protein 175 / hTMEM175


Mass: 55667.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM175
Production host: Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)
References: UniProt: Q9BSA9

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Non-polymers , 5 types, 41 molecules

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


Mass: 364.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21FO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1ETE / (2S)-2-butyl-2-cyclohexyl-6,7-bis(fluoranyl)-5-[3-(1H-1,2,3,4-tetrazol-5-yl)propoxy]-3H-inden-1-one


Mass: 432.507 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H30F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: DCY1020-bound structure of TMEM175 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DARK FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 1.38 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 249064 / Symmetry type: POINT

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