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TitleStructure of the human TWIK-2 potassium channel and its inhibition by pimozide.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 19, Page e2425709122, Year 2025
Publish dateMay 13, 2025
AuthorsNandish K Khanra / Chongyuan Wang / Bryce D Delgado / Stephen B Long /
PubMed AbstractThe potassium channel TWIK-2 is crucial for ATP-induced activation of the NLRP3 inflammasome in macrophages. The channel is a member of the two-pore domain potassium (K2P) channel superfamily and an ...The potassium channel TWIK-2 is crucial for ATP-induced activation of the NLRP3 inflammasome in macrophages. The channel is a member of the two-pore domain potassium (K2P) channel superfamily and an emerging therapeutic target to mitigate severe inflammatory injury involving NLRP3 activation. We report the cryo-EM structure of human TWIK-2. In comparison to other K2P channels, the structure reveals an unusual "up" conformation of Tyr111 in the selectivity filter and a resulting SF1-P1 pocket behind the filter. Density for acyl chains is present in fenestrations within the transmembrane region that connects the central cavity of the pore to the lipid membrane. Despite its importance as a drug target, limited pharmacological tools are available for TWIK-2. A previous study suggested that the FDA-approved small molecule pimozide might inhibit TWIK-2. Using a reconstituted system, we show that pimozide directly inhibits the channel and we determine a cryo-EM structure of a complex with the drug. Pimozide displaces the acyl chains within the fenestrations and binds below the selectivity filter where it would impede ion permeation. The drug may access its binding site by lateral diffusion in the membrane, suggesting that other hydrophobic small molecules could have utility for inhibiting TWIK-2. The work defines the structure of TWIK-2 and provides a structural foundation for development of more specific inhibitors with potential utility as anti-inflammatory drugs.
External linksProc Natl Acad Sci U S A / PubMed:40343992 / PubMed Central
MethodsEM (single particle)
Resolution2.85 - 3.17 Å
Structure data

48216

9mek

EMDB-48216, PDB-9mek:
Structure of the human TWIK-2 potassium channel
Method: EM (single particle) / Resolution: 2.85 Å

48217

9mel

EMDB-48217, PDB-9mel:
Structure of the human TWIK-2 potassium channel in complex with pimozide
Method: EM (single particle) / Resolution: 3.17 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-HP6:
HEPTANE

ChemComp-1II:
3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Two-pore potassium channel K2P6 TWIK2 K2P channel / Two-pore potassium channel K2P6 TWIK2 K2P channel pimozide drug NLRP3 inflammasome

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