10 research outputs found
K(2P)2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site
Polymodal thermo- and mechanosensitive two-pore domain potassium (K-2P)
channels of the TREK1 subfamily generate `leak' currents that regulate
neuronal excitability, respond to lipids, temperature and mechanical
stretch, and influence pain, temperature perception and anaesthetic
responses(1-3). These dimeric voltage-gated ion channel (VGIC)
superfamily members have a unique topology comprising two pore-forming
regions per subunit(4-6). In contrast to other potassium channels, K-2P
channels use a selectivity filter `C-type' gate(7-10) as the principal
gating site. Despite recent advances(3,11,12), poor pharmacological
profiles of K2P channels limit mechanistic and biological studies. Here
we describe a class of small-molecule TREK activators that directly
stimulate the C-type gate by acting as molecular wedges that restrict
interdomain interface movement behind the selectivity filter. Structures
of K(2P)2.1 (also known as TREK-1) alone and with two selective K(2P)2.1
(TREK-1) and K(2P)10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335,
and a thiophene-carboxamide, ML402-define a cryptic binding pocket
unlike other ion channel small-molecule binding sites and, together with
functional studies, identify a cation-p interaction that controls
selectivity. Together, our data reveal a druggable K-2P site that
stabilizes the C-type gate `leak mode' and provide direct evidence for
K-2P selectivity filter gating