Structural basis of rapid inactivation of HERG potassium channels.

Abstract

The exquisite fine tuning of electrical signalling in different cells types is mediated by variations in the rates that gates open and close in different ion channels. The opening and closing of the inactivation gate in Human ether-a-go-go related gene (HERG) K+ channels is uniquely rapid, which confers upon them a critical role in protecting against cardiac arrhythmias and sudden cardiac death. The molecular mechanisms that underlie the rapidity of HERG inactivation, however, remain unclear. Here, we have determined Cryo-EM structures of the conductive state as well as HERG's elusive inactivated state to 2.4 Å resolution and propose a mechanism for the fast kinetics of inactivation. The selectivity filter is pulled upward by Asn633 upon the exit of potassium ions from the upper part of the filter. This movement allows the sidechain of Ser620, located behind the selectivity filter, to alternately hydrogen bond to the upper or lower part of the selectivity filter to stabilize the conducting and inactivated states respectively. The inactivated state is also characterized by flipping of the valine carbonyls in the centre of the selectivity filter. Using molecular dynamics simulation, we have identified a transient interaction between Ser620 and Tyr616 that reduces the free energy barrier for flipping of the valine carbonyls, thereby explaining the rapidity of HERG inactivation. Our results have demonstrated the dynamic nature of potassium channels with a new model of inactivation different from the well characterized KcsA.