Structural basis for differential inhibition of THIK1 by chemically related inhibitors
- 1Fudan University
Abstract
TWIK-related halothane-inhibited potassium channel 1 (THIK1) is a two-pore domain potassium (K2P) channel highly expressed in microglia that contributes to microglial homeostasis and neuroinflammatory responses. Pharmacological inhibition of THIK1 suppresses tonic K+ currents and attenuates NLRP3-dependent IL-1{beta} release, highlighting THIK1 as a potential therapeutic target for neuroinflammatory disorders. However, the structural basis of THIK1 inhibition remains unclear. Here we report cryo-electron microscopy (cryo-EM) structures of full-length human THIK1 in complex with C101248, a commercially available tool compound, and CVN293, a clinical-stage inhibitor that has completed Phase I evaluation. The two inhibitors occupy a similar site within the inner vestibule formed by TM2 and TM4 beneath the selectivity filter. Consistent with their closely related chemical scaffolds and shared binding site, both inhibitors remodel the Y273 inner gate but differ in their effects on the C-terminal gate. Electrophysiological analyses further demonstrate that the C-terminal gate contributes differently to inhibition by the two compounds. Together, our findings show how chemically related inhibitors exert different effects on THIK1 despite engaging a common binding site.
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BibTeX
@misc{zhang2026structural,
title = {{Structural basis for differential inhibition of THIK1 by chemically related inhibitors}},
author = {R. Zhang and X. Fang and R. Zhang and Z. Wang and H. Jin and B. Wang and W. Wang and X. Zhong and J. Wang and B. Li},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753137},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753137v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural basis for differential inhibition of THIK1 by chemically related inhibitors
AU - R. Zhang
AU - X. Fang
AU - R. Zhang
AU - Z. Wang
AU - H. Jin
AU - B. Wang
AU - W. Wang
AU - X. Zhong
AU - J. Wang
AU - B. Li
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753137
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753137v1
AB - TWIK-related halothane-inhibited potassium channel 1 (THIK1) is a two-pore domain potassium (K2P) channel highly expressed in microglia that contributes to microglial homeostasis and neuroinflammatory responses. Pharmacological inhibition of THIK1 suppresses tonic K+ currents and attenuates NLRP3-dependent IL-1{beta} release, highlighting THIK1 as a potential therapeutic target for neuroinflammatory disorders. However, the structural basis of THIK1 inhibition remains unclear. Here we report cryo-electron microscopy (cryo-EM) structures of full-length human THIK1 in complex with C101248, a commercially available tool compound, and CVN293, a clinical-stage inhibitor that has completed Phase I evaluation. The two inhibitors occupy a similar site within the inner vestibule formed by TM2 and TM4 beneath the selectivity filter. Consistent with their closely related chemical scaffolds and shared binding site, both inhibitors remodel the Y273 inner gate but differ in their effects on the C-terminal gate. Electrophysiological analyses further demonstrate that the C-terminal gate contributes differently to inhibition by the two compounds. Together, our findings show how chemically related inhibitors exert different effects on THIK1 despite engaging a common binding site.
ER -