K2P pore region structure. (a) Sequence alignment of selectivity filter and loop regions of PD1 and PD2 for the indicated channels. P1, M2, P2, and M4 helices (blue), SF1 and SF2 (orange), SF1-M2 loop (red), and SF2-M4 loop (light blue) are indicated. Terminal residue of the selectivity filter is highlighted. (b) Superposition of the selectivity filters and permeant ions for: K2P1.1 (TWIK-1) (3UKM)36 (red), K2P2.1 (TREK-1) (6CQ6)37 (smudge), K2P2.1 (TREK1):ML335 (6CQ8)37 (deep salmon), K2P2.1 (TREK-1):ML402 (6CQ9),37 K2P3.1 (TASK-1) (6RV2) (orange),38 K2P3.1 (TASK-1):BAY1000493 (6RV3) (yellow orange),38 K2P3.1 (TASK-1):BAY2341237(6RV4) (olive),38 K2P4.1 (TRAAK) (3UM7)39 (aquamarine), (4I9W)56 (limon), (4WFE) (forest green),58 (4WFF) (white),58 (4WFG) (grey),58 (4WFH) (black),58 K2P4.1 (TRAAK) G124I (4RUE) (blue)57, K2P4.1 (TRAAK) W262S (4RUF) (lime green),57 K2P5.1 (TASK-2) pH 6.5 (6WLV) (deep olive),41 K2P5.1 (TASK-2) pH 8.5 (6WM0) (light teal),41 K2P10.1 (TREK-2) (4BW5)40 (pink), (4XDJ)40 (magenta), (4XDK)40 (purple). SF1, SF2 and ion binding positions, S1-S4, are indicated. Ions are shown as spheres and colored according to the parent structure. (c) K2P pore domains (PD1 and PD2) highlighting the inherent heterotetrameric nature of the pore and the domain-swapped positions of M1. (d) Superposition of K2P2.1 (TREK-1) (PDB:6CQ6)37 P1-SF1-M2 (orange) and P2-SF2-M4 (slate). SF1-M2 loop (red) and SF2-M4 loop (blue) and portions having a shared conformation (dark blue) are indicated. Residue labels indicate the SF1-M2 and SF2-M4 loop ends and structural divergence point (Pro150/Ala259). GenBank sequences in ‘a’ are: K2P2.1 (TREK-1), AAD47569.1; K2P10.1 (TREK-2), AAL95705.1; K2P4.1 (TRAAK), AAF64062.1; K2P3.1 (TASK-1), AAC51777.1; K2P9.1 (TASK-3), AAF63708.1; K2P15.1 (TASK-5), AAG33127.1; K2P5.1 (TASK-2), AAC79458.1; K2P16.1 (TALK-1), AAK49532.1; K2P17.1 (TALK-2), AAK49533.1; K2P1.1 (TWIK-1), AAB01688.1, K2P6.1 (TWIK-2), AAD22980.1; K2P12.1 (THIK-2), AAG32313.1; K2P13.1 (THIK-1), AAG32314.1; K2P18.1 (TRESK), BAC78527.1.