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TitleDiscovery and structural basis of endogenous and exogenous inhibitors of the proton-activated-chloride channel.
Journal, issue, pagesCell Rep, Vol. 44, Issue 7, Page 115998, Year 2025
Publish dateJul 22, 2025
AuthorsHeng 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 /
PubMed AbstractThe 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.
External linksCell Rep / PubMed:40664207
MethodsEM (single particle)
Resolution2.89 - 3.85 Å
Structure data

60224

8zlb

EMDB-60224, PDB-8zlb:
EB bound state of hPAC
Method: EM (single particle) / Resolution: 3.85 Å

60228

8zll

EMDB-60228, PDB-8zll:
The apo state of hPAC with endogenous cholesterol
Method: EM (single particle) / Resolution: 2.89 Å

63102

9lhm

EMDB-63102, PDB-9lhm:
hPAC structure in the presence of MbCD
Method: EM (single particle) / Resolution: 3.43 Å

63110

9li2

EMDB-63110, PDB-9li2:
DCA-bound state of hPAC structure
Method: EM (single particle) / Resolution: 3.72 Å

Chemicals

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

ChemComp-CLR:
CHOLESTEROL

ChemComp-DXC:
(3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID / detergent*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / hPAC / EVANS BLUE / STRUCTUAL PROTEIN / PAC / DCA

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