S5–pore loop–S6 segments of the BK channel and the relative size of the paxilline molecule. (A) A homology model of the BK channel S5–pore loop–S6 structure was generated based on alignment with Kv1.2 and the available Kv1.2 crystal structure. Coloring identifies segments used for generation of chimeras as follows: red, S5; yellow, first half of pore loop; blue, second half of pore loop, including so-called turret; gray, S6. Orange residues are those that influence iberiotoxin binding (Giangiacomo et al., 2008). G311 in S6 is highlighted in magenta. A space-filling model of paxilline (to the same scale) is positioned adjacent to an S5 helix, but this positioning is not meant to imply anything about the position of paxilline in a blocking site. Note that the actual topology of the BK turret is entirely unknown. Furthermore, this cartoon does not take into account the likely large width of the BK central cavity. (B) The chemical structure of paxilline is shown.