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.
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