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- EMDB-63102: hPAC structure in the presence of MbCD -

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Basic information

Entry
Database: EMDB / ID: EMD-63102
TitlehPAC structure in the presence of MbCD
Map datahPAC in the presence of MbCD
Sample
  • Complex: structure of hPAC in the presence of MbCD
    • Protein or peptide: Proton-activated chloride channel
KeywordsPAC / structual protein / MEMBRANE PROTEIN
Function / homologypH-gated chloride channel activity / TMEM206 protein / TMEM206 protein family / chloride transport / chloride channel complex / cell surface / plasma membrane / Proton-activated chloride channel
Function and homology information
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsZhang H / Chen X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122040 China
CitationJournal: Cell Rep / Year: 2025
Title: Discovery and structural basis of endogenous and exogenous inhibitors of the proton-activated-chloride channel.
Authors: Heng Zhang / Zhijun Zhao / Xiaoying Chen / Qingxia Ma / Wenxuan Zhen / Qianqian Xu / Yaqi Wang / Bingyu He / Ying Huang / Pengfei Xu / Haoxing Xu / Zhimin Lu / Nannan Su / Fan Yang /
Abstract: The proton-activated chloride (PAC) channel is a broadly expressed chloride channel that senses extracellular acidification, regulates endosomal acidification, and participates in many processes, ...The proton-activated chloride (PAC) channel is a broadly expressed chloride channel that senses extracellular acidification, regulates endosomal acidification, and participates in many processes, including acid-induced cell death and cancer cell migration. However, the lack of specific modulators has limited our understanding of its function and therapeutic potential. Here, we discovered that endogenous cholesterol (CHL) partially inhibits PAC channel activation. Moreover, we identified a series of CHL analogs and structurally related dyes as full antagonists of the PAC channel, with deoxycholic acid (DCA) and Evans blue (EB) as their representative compounds. By combining cryo-electron microscopy (cryo-EM) and patch-clamp recordings, we revealed the distinct binding and inhibition mechanisms of DCA and EB on this channel. Moreover, in malignant osteosarcoma cells, where PAC channel expression is upregulated, EB inhibited the migration and invasion of these cells. Therefore, we identified DCA and EB as pharmacological tools for the PAC channel, which forms a basis for future drug discovery targeting this channel.
History
DepositionJan 12, 2025-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63102.png

Downloads & links

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Map

FileDownload / File: emd_63102.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationhPAC in the presence of MbCD
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.7659146 - 1.0612502
Average (Standard dev.)0.00030256165 (±0.021240104)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_63102_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_63102_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : structure of hPAC in the presence of MbCD

EntireName: structure of hPAC in the presence of MbCD
Components
  • Complex: structure of hPAC in the presence of MbCD
    • Protein or peptide: Proton-activated chloride channel

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Supramolecule #1: structure of hPAC in the presence of MbCD

SupramoleculeName: structure of hPAC in the presence of MbCD / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Proton-activated chloride channel

MacromoleculeName: Proton-activated chloride channel / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.681938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKW SHPQFEKGGG GSGGSAWSHP QFEKEFKGLV DMIRQERSTS YQELSEELVQ VVENSELADE QDKETVRVQG PGILPGLDS ESASSSIRFS KACLKNVFSV LLIFIYLLLM AVAVFLVYRT ITDFREKLKH PVMSVSYKEV DRYDAPGIAL Y PGQAQLLS ...String:
MDYKDDDDKW SHPQFEKGGG GSGGSAWSHP QFEKEFKGLV DMIRQERSTS YQELSEELVQ VVENSELADE QDKETVRVQG PGILPGLDS ESASSSIRFS KACLKNVFSV LLIFIYLLLM AVAVFLVYRT ITDFREKLKH PVMSVSYKEV DRYDAPGIAL Y PGQAQLLS CKHHYEVIPP LTSPGQPGDM NCTTQRINYT DPFSNQTVKS ALIVQGPREV KKRELVFLQF RLNKSSEDFS AI DYLLFSS FQEFLQSPNR VGFMQACESA YSSWKFSGGF RTWVKMSLVK TKEEDGREAV EFRQETSVVN YIDQRPAAKK SAQ LFFVVF EWKDPFIQKV QDIVTANPWN TIALLCGAFL ALFKAAEFAK LSIKWMIKIR KRYLKRRGQA TSHIS

UniProtKB: Proton-activated chloride channel

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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: 5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average exposure time: 4.5 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 78614
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: OTHER
Output model

PDB-9lhm:
hPAC structure in the presence of MbCD

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