Side Fenestrations Provide an “Anchor” for a Stable Binding of A1899 to the Pore of TASK‑1 Potassium Channels

A1899 is a potent and selective inhibitor
of the two-pore domain
potassium (K2P) channel TASK-1. It was previously reported
that A1899 acts as an open-channel blocker and binds to residues of
the P1 and P2 regions, the M2 and M4 segments, and the halothane response
element. The recently described crystal structures of K2P channels together with the newly identified side fenestrations indicate
that residues relevant for TASK-1 inhibition are not purely facing
the central cavity as initially proposed. Accordingly, the TASK-1
binding site and the mechanism of inhibition might need a re-evaluation.
We have used TASK-1 homology models based on recently crystallized
K2P channels and molecular dynamics simulation to demonstrate
that the highly potent TASK-1 blocker A1899 requires binding to residues
located in the side fenestrations. Unexpectedly, most of the previously
described residues that interfere with TASK-1 blockade by A1899 project
their side chains toward the fenestration lumina, underlining the
relevance of these structures for drug binding in K2P channels.
Despite its hydrophobicity, A1899 does not seem to use the fenestrations
to gain access to the central cavity from the lipid bilayer. In contrast,
binding of A1899 to residues of the side fenestrations might provide
a physical “anchor”, reflecting an energetically favorable
binding mode that after pore occlusion stabilizes the closed state
of the channels.