Potassium channels allow for the passive movement of potassium ions across the
cell membrane and are instrumental in controlling the membrane potential in all
cell types. Quaternary ammonium (QA) compounds block potassium channels and have
long been used to study the functional and structural properties of these
channels. Here we describe the interaction between three symmetrical hydrophobic
QAs and the prokaryotic potassium channel KcsA. The structures demonstrate the
presence of a hydrophobic pocket between the inner helices of KcsA and provide
insight into the binding site and blocking mechanism of hydrophobic QAs. The
structures also reveal a structurally hidden pathway between the central cavity
and the outside membrane environment reminiscent of the lateral fenestration
observed in sodium channels that can be accessed through small conformational
changes in the pore wall. We propose that the hydrophobic binding pocket
stabilizes the alkyl chains of long-chain QA molecules and may play a key role
in hydrophobic drug binding in general.
