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- PDB-9li2: DCA-bound state of hPAC structure -

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Basic information

Entry
Database: PDB / ID: 9li2
TitleDCA-bound state of hPAC structure
ComponentsProton-activated chloride channel
KeywordsMEMBRANE PROTEIN / hPAC / DCA / STRUCTUAL 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.72 Å
AuthorsZhang, H. / Chen, X.
Funding support China, 1items
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 13, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 6, 2025Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proton-activated chloride channel
B: Proton-activated chloride channel
C: Proton-activated chloride channel
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,2246
Polymers134,0463
Non-polymers1,1783
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Proton-activated chloride channel / PAC / hPAC / Acid-sensitive outwardly-rectifying anion channel / ASOR / Proton-activated outwardly ...PAC / hPAC / Acid-sensitive outwardly-rectifying anion channel / ASOR / Proton-activated outwardly rectifying anion channel / PAORAC / Transmembrane protein 206 / hTMEM206


Mass: 44681.938 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PACC1, C1orf75, TMEM206 / Production host: Homo sapiens (human) / References: UniProt: Q9H813
#2: Chemical ChemComp-DXC / (3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID / DEOXYCHOLIC ACID


Mass: 392.572 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H40O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: detergent*YM
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: Complex of hPAC and DCA / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.72 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 80746 / Symmetry type: POINT

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