9MUH

Mus musculus TASK-1 (KCNK3) in MSP1E3D1 lipid nanodisc at pH 6.0 and 100 mM KCl

Summary for 9MUH

• Entry DOI: 10.2210/pdb9muh/pdb
• EMDB information: 48632
• Descriptor: Potassium channel subfamily K member 3, POTASSIUM ION, CHOLESTEROL HEMISUCCINATE (3 entities in total)
• Functional Keywords: k2p, membrane protein, potassium channel, ion channel
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 61474.07

Authors

Docter, T.A.,Brohawn, S.G. (deposition date: 2025-01-13, release date: 2026-01-28, Last modification date: 2026-06-17)

Primary citation

Docter, T.,Lee, N.S.,Reid, M.S.,Brohawn, S.G.
Structural basis for proton inhibition of the two-pore domain K + channel TASK-1.
Structure, 2026

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 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.

PubMed: 42229429
DOI: 10.1016/j.str.2026.05.002

Experimental method

ELECTRON MICROSCOPY (3.1 Å)