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- EMDB-43257: AP-6 bound human TMEM175 -

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Basic information

Entry
Database: EMDB / ID: EMD-43257
TitleAP-6 bound human TMEM175
Map dataAP-6 bound TMEM175
Sample
  • Complex: human TMEM175 in an inhibitor-bound state
    • Protein or peptide: Endosomal/lysosomal potassium channel TMEM175
  • Ligand: (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine)
KeywordsIon Channel / Lysosome / Potassium Channel / TRANSPORT 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 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.48 Å
AuthorsOh S / Hite RK
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseAug 14, 2024-
Map releaseAug 14, 2024-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43257.png

Downloads & links

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Map

FileDownload / File: emd_43257.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAP-6 bound TMEM175
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 384 pix.
= 316.992 Å		0.83 Å/pix.
x 384 pix.
= 316.992 Å		0.83 Å/pix.
x 384 pix.
= 316.992 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8255 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 6.0
Minimum - Maximum-61.593940000000003 - 72.855490000000003
Average (Standard dev.)0.000000000001391 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 316.992 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A

Fileemd_43257_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_43257_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human TMEM175 in an inhibitor-bound state

EntireName: human TMEM175 in an inhibitor-bound state
Components
  • Complex: human TMEM175 in an inhibitor-bound state
    • Protein or peptide: Endosomal/lysosomal potassium channel TMEM175
  • Ligand: (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine)

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Supramolecule #1: human TMEM175 in an inhibitor-bound state

SupramoleculeName: human TMEM175 in an inhibitor-bound state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: AP-6 bound TMEM175
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55 kDa/nm

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Macromolecule #1: Endosomal/lysosomal potassium channel TMEM175

MacromoleculeName: Endosomal/lysosomal potassium 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: Homo sapiens (human)
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: (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine)

MacromoleculeName: (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine) / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1AA3
Molecular weightTheoretical: 262.309 Da

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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

Concentration4 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
0.1 %lauryl maltose neopentyl glycol
50.0 mMTris pH 8.0
150.0 mMPotassium ChlorideKCl
2.0 mMDithiothreitol
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: Blot for 4 seconds prior to plunging.
DetailsDimeric channels

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-40 / Number grids imaged: 2 / Average exposure time: 3.0 sec. / Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3220435
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6wc9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 215519
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 3.2)
Final angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 3.2)
Final 3D classificationNumber classes: 1 / Software - Name: cryoSPARC (ver. 3.2)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER / Target criteria: FSC
Output model

PDB-8vic:
AP-6 bound human TMEM175

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