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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
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Structure of the human TWIK-2 potassium channel and its inhibition by pimozide

Nandish K Khanra, Chongyuan Wang, Bryce D Delgado

    Biorxiv : the Preprint Server for Biology
    |March 10, 2025
    PubMed

    Insights

    Researchers determined the cryo-EM structure of the TWIK-2 potassium channel, revealing unique features and a binding site for inhibitors. The drug pimozide was found to inhibit TWIK-2, offering a foundation for new anti-inflammatory therapies.

    Area of Science:

    • Structural Biology
    • Ion Channel Physiology
    • Drug Discovery

    Background:

    • The TWIK-2 potassium channel (a member of the K2P channel superfamily) plays a critical role in NLRP3 inflammasome activation.
    • NLRP3 inflammasome activation is implicated in severe inflammatory injuries.
    • There is a need for pharmacological tools to modulate TWIK-2 activity.

    Purpose of the Study:

    • To determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human TWIK-2.
    • To identify potential binding sites for small molecule modulators.
    • To investigate the inhibitory effect of pimozide on TWIK-2 and elucidate its binding mechanism.

    Main Methods:

    • Cryo-electron microscopy (cryo-EM) for structure determination.
    • Biochemical assays to assess channel inhibition.
    • Structural analysis of TWIK-2 and its complex with pimozide.

    Main Results:

    • The cryo-EM structure of human TWIK-2 revealed unique features, including a specific Tyr111 conformation and an SF1-P1 pocket.
    • Acyl chains were observed within fenestrations in the transmembrane region.
    • Pimozide was identified as a TWIK-2 inhibitor, binding below the selectivity filter and blocking ion conduction.
    • The structure of the TWIK-2-pimozide complex elucidated the drug's binding site and inhibitory mechanism.

    Conclusions:

    • The determined structure of TWIK-2 provides a foundation for developing specific inhibitors.
    • Pimozide's inhibition mechanism suggests that hydrophobic small molecules could be effective TWIK-2 modulators.
    • These findings support the development of TWIK-2 inhibitors as potential anti-inflammatory therapeutics for diseases involving NLRP3 activation.

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