Fig. 4. A293 binds to the lower central cavity at the lateral entry to the side fenestrations. (a-d) A293 binding modes in a TWIK-1-based TASK-1 homology model. Illustrated are all 30 docking solutions of the two significant clusters that we obtained, with 19 and 11 docking solutions, respectively. (a) Bottom view of A293 located in the central cavity in close proximity to Q126, L239 and N240. (b) Similar display as in (a) illustrating the surface area and the side fenestrations (LF). Note that A293 directly binds in front of the entry to the LF, interacting with L239 located in the fenestrations. (c) Zoom into the central cavity illustrating the poses of the two significant clusters and the residues that we identified with the alanine scanning mutagenesis. (d) Similar zoom-in but view from inside the cell. Note that A293 is able to interact with L239 of both fenestrations (distance less than 4 Å). (e) Best docking solution of A293 in the TASK-1 homology model and zoom-ins to illustrate the interactions of A293 with (f) Q126, (g) the L239 residue of both subunits and (h) N240.