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| Title | Structural basis for proton inhibition of the two-pore domain K channel TASK-1. |
|---|---|
| Journal, issue, pages | Structure, Year 2026 |
| Publish date | Jun 2, 2026 |
 Authors | Trevor Docter / Nicolas S Lee / Michelle S Reid / Stephen G Brohawn /  |
| PubMed Abstract | TASK-1 is a pH-sensitive two-pore domain K channel implicated in diseases including pulmonary arterial hypertension (PAH) and developmental delay with sleep apnea (DDSA). Structures of TASK-1 have ...TASK-1 is a pH-sensitive two-pore domain K channel implicated in diseases including pulmonary arterial hypertension (PAH) and developmental delay with sleep apnea (DDSA). Structures of TASK-1 have been captured with an open external gate, but the structural basis for external proton inhibition is incompletely understood. Here, we present a cryo-EM structure of TASK-1 at pH 6.0 and 100 mM K, revealing a closed extracellular gate. pH-regulation of TASK-1 involves a C-type selectivity filter gate similar to TASK-3, but distinct from other K2Ps, in which histidine protonation leads to the formation of a hydrophobic seal above the filter. We find that a PAH-associated loss-of-function mutation near the outer gate increases proton sensitivity, while DDSA-associated and other gain-of-function mutations near the inner X-gate and cavity reduce proton sensitivity. These data reveal the mechanism for pH regulation of TASK-1, illustrate differences in C-type gating among K2Ps, and suggest allosteric communication between inner and outer gates. |
 External links | Structure / PubMed:42229429 |
| Methods | EM (single particle) |
| Resolution | 3.1 Å |
| Structure data | EMDB-48632, PDB-9muh: |
| Chemicals |  ChemComp-K:  ChemComp-Y01: |
| Source |
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 Keywords | MEMBRANE PROTEIN / K2P / POTASSIUM CHANNEL / ION CHANNEL |
mus musculus (house mouse)