Potassium dependent structural changes in the selectivity filter of HERG potassium channels

The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we have exploited the K ⁺ sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. We propose that inactivation is the result of a high propensity for flipping of the selectivity filter valine carbonyl oxygens. Molecular dynamics simulations point to a low energy barrier, and hence rapid kinetics, for flipping of the valine 625 carbonyl oxygens facilitated by a previously unrecognized interaction between S620 and Y616 that stabilizes the transition state between conducting and non-conducting structures. Our model represents a new mechanism by which ion channels fine tune their activity that explains the uniquely rapid inactivation kinetics of HERG.