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- EMDB-60224: EB bound state of hPAC -

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Basic information

Entry
Database: EMDB / ID: EMD-60224
TitleEB bound state of hPAC
Map data
Sample
  • Complex: Complex of hPAC and EB
    • Protein or peptide: Proton-activated chloride channel
  • Ligand: 4-azanyl-6-[[4-[4-[(~{E})-(8-azanyl-1-oxidanyl-5,7-disulfo-naphthalen-2-yl)diazenyl]-3-methyl-phenyl]-2-methyl-phenyl]diazenyl]-5-oxidanyl-naphthalene-1,3-disulfonic acid
KeywordshPAC / EVANS BLUE / 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: 3.85 Å
AuthorsSu N / 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
DepositionMay 18, 2024-
Header (metadata) releaseJul 23, 2025-
Map releaseJul 23, 2025-
UpdateAug 6, 2025-
Current statusAug 6, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60224.png

Downloads & links

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Map

FileDownload / File: emd_60224.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.)
1.01 Å/pix.
x 256 pix.
= 259.584 Å		1.01 Å/pix.
x 256 pix.
= 259.584 Å		1.01 Å/pix.
x 256 pix.
= 259.584 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-1.1874151 - 1.9887887
Average (Standard dev.)-0.00057926 (±0.021209447)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 259.584 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60224_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60224_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of hPAC and EB

EntireName: Complex of hPAC and EB
Components
  • Complex: Complex of hPAC and EB
    • Protein or peptide: Proton-activated chloride channel
  • Ligand: 4-azanyl-6-[[4-[4-[(~{E})-(8-azanyl-1-oxidanyl-5,7-disulfo-naphthalen-2-yl)diazenyl]-3-methyl-phenyl]-2-methyl-phenyl]diazenyl]-5-oxidanyl-naphthalene-1,3-disulfonic acid

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Supramolecule #1: Complex of hPAC and EB

SupramoleculeName: Complex of hPAC and EB / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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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Macromolecule #2: 4-azanyl-6-[[4-[4-[(~{E})-(8-azanyl-1-oxidanyl-5,7-disulfo-naphth...

MacromoleculeName: 4-azanyl-6-[[4-[4-[(~{E})-(8-azanyl-1-oxidanyl-5,7-disulfo-naphthalen-2-yl)diazenyl]-3-methyl-phenyl]-2-methyl-phenyl]diazenyl]-5-oxidanyl-naphthalene-1,3-disulfonic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: IZ8
Molecular weightTheoretical: 872.878 Da
Chemical component information

ChemComp-IZ8:
4-azanyl-6-[[4-[4-[(~{E})-(8-azanyl-1-oxidanyl-5,7-disulfo-naphthalen-2-yl)diazenyl]-3-methyl-phenyl]-2-methyl-phenyl]diazenyl]-5-oxidanyl-naphthalene-1,3-disulfonic acid

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average exposure time: 8.0 sec. / Average electron dose: 62.0 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: 1.5 µm / Nominal defocus min: 1.0 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: 3.85 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 212540
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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