Structure of the human TWIK-2 potassium channel and its inhibition by pimozide Journal Article
| Authors: | Khanra, N. K.; Wang, C.; Delgado, B. D.; Long, S. B. |
| Article Title: | Structure of the human TWIK-2 potassium channel and its inhibition by pimozide |
| Abstract: | 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. Copyright © 2025 the Author(s). |
| Keywords: | genetics; protein conformation; metabolism; chemistry; models, molecular; molecular model; pimozide; cryoelectron microscopy; therapeutic; potassium channel; potassium channels, tandem pore domain; nlrp3 inflammasome; humans; human; k2p channel; k2p6; potassium channel blockers; potassium channel blocking agent; tandem pore domain potassium channel |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 19 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-05-19 |
| Start Page: | e2425709122 |
| Language: | English |
| DOI: | 10.1073/pnas.2425709122 |
| PUBMED: | 40343992 |
| PROVIDER: | scopus |
| PMCID: | PMC12088453 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Stephen Long -- Source: Scopus |
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