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- PDB-8vic: AP-6 bound human TMEM175 -

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Basic information

Entry
Database: PDB / ID: 8vic
TitleAP-6 bound human TMEM175
ComponentsEndosomal/lysosomal potassium channel TMEM175
KeywordsTRANSPORT PROTEIN / Ion Channel / Lysosome / Potassium Channel
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 / endosome membrane / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.48 Å
AuthorsOh, S. / Hite, R.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA008748 United States
CitationJournal: J Am Chem Soc / Year: 2024
Title: Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175.
Authors: SeCheol Oh / Jooyeon Lee / Ho Jeong Choi / Songwon Kim / Vinay Sapuru / Min Kim / Richard K Hite /
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 ...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.
History
DepositionJan 3, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
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Revision 1.1Feb 26, 2025Group: Data collection / Database references / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)111,5973
Polymers111,3342
Non-polymers2621
Water00
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

#1: Protein Endosomal/lysosomal potassium channel TMEM175


Mass: 55667.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM175 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q9BSA9
#2: Chemical ChemComp-A1AA3 / (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine)


Mass: 262.309 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14N4 / Feature type: SUBJECT OF INVESTIGATION
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: human TMEM175 in an inhibitor-bound state / Type: COMPLEX / Details: AP-6 bound TMEM175 / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 55 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
10.1 %lauryl maltose neopentyl glycol1
250 mMTris pH 8.01
3150 mMPotassium ChlorideKCl1
42 mMDithiothreitol1
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Dimeric channels
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K / Details: Blot for 4 seconds prior to plunging

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingAverage exposure time: 3 sec. / Electron dose: 66 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2
Image scansMovie frames/image: 40 / Used frames/image: 1-40

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Processing

EM software
IDNameVersionCategory
1RELION3.1particle selection
2SerialEMimage acquisition
4CTFFIND4.1.13CTF correction
7PHENIXdev-3751model fitting
9PHENIXdev-3751model refinement
10cryoSPARC3.2initial Euler assignment
11cryoSPARC3.2final Euler assignment
12cryoSPARC3.2classification
13cryoSPARC3.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3220435
3D reconstructionResolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215519 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL / Target criteria: FSC
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045692
ELECTRON MICROSCOPYf_angle_d0.4727756
ELECTRON MICROSCOPYf_dihedral_angle_d6.339766
ELECTRON MICROSCOPYf_chiral_restr0.035956
ELECTRON MICROSCOPYf_plane_restr0.005945

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