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Structure of the human TWIK-2 potassium channel and its inhibition by pimozide

Nandish K Khanra1, Chongyuan Wang1, Bryce D Delgado1,2

  • 1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

Proceedings of the National Academy of Sciences of the United States of America
|May 9, 2025
PubMed

Insights

The potassium channel TWIK-2, vital for inflammasome activation, has its structure revealed by cryo-EM. The drug pimozide directly inhibits TWIK-2, offering a potential anti-inflammatory therapeutic strategy.

Area of Science:

  • Structural biology
  • Molecular pharmacology
  • Immunology

Background:

  • The potassium channel TWIK-2 (Twik-related intermal potassium channel 2) is essential for ATP-induced activation of the NLRP3 inflammasome in macrophages.
  • TWIK-2, a member of the two-pore domain potassium (K2P) channel superfamily, is an emerging therapeutic target for inflammatory diseases.
  • Limited pharmacological tools exist for TWIK-2, hindering the development of anti-inflammatory drugs.

Purpose of the Study:

  • To determine the cryo-electron microscopy (cryo-EM) structure of human TWIK-2.
  • To investigate the inhibitory mechanism of pimozide on TWIK-2.
  • To provide a structural basis for developing novel TWIK-2 inhibitors.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) for structural determination.
  • Reconstituted channel system for functional assays.
  • Pimozide inhibition assays.

Main Results:

  • The cryo-EM structure of human TWIK-2 revealed an unusual conformation of Tyr111 in the selectivity filter and acyl chains in transmembrane fenestrations.
  • Pimozide was shown to directly inhibit TWIK-2 by binding below the selectivity filter, displacing acyl chains.
  • The structure of the TWIK-2-pimozide complex suggests potential drug access via lateral membrane diffusion.

Conclusions:

  • The determined structure of TWIK-2 provides critical insights into its architecture and function.
  • Pimozide directly inhibits TWIK-2, validating it as a potential anti-inflammatory therapeutic target.
  • The findings lay the groundwork for designing specific TWIK-2 inhibitors for inflammatory conditions.
Keywords:
K2P channelK2P6NLRP3 inflammasomepotassium channeltherapeutic

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