Isoleucine gate blocks K+ conduction in C-type inactivation

Many voltage-gated potassium (Kv) channels display a time-dependent phenomenon called C-type inactivation, whereby prolonged activation by voltage leads to the inhibition of ionic conduction, a process that involves a conformational change at the selectivity filter toward a non-conductive state. Recently, a high-resolution structure of a strongly inactivating triple-mutant channel kv1.2-kv2.1-3m revealed a novel conformation of the selectivity filter that is dilated at its outer end, distinct from the well-characterized conductive state. While the experimental structure was interpreted as the elusive non-conductive state, molecular dynamics simulations and electrophysiology measurements demonstrate that the dilated filter of kv1.2-kv2.1-3m, however, is conductive and, as such, cannot completely account for the inactivation of the channel observed in functional experiments. An additional conformational change implicating isoleucine residues at position 398 along the pore lining segment S6 is required to effectively block ion conduction. It is shown that the I398 residues from the four subunits act as a state-dependent hydrophobic gate located immediately beneath the selectivity filter. As a critical piece of the C-type inactivation machinery, this structural feature is the potential target of a broad class of QA blockers and negatively charged activators thus opening new research directions towards the development of drugs that specifically modulate gating-states of Kv channels.