A KcsA-hERG Chimera Provides Structural Insights into the Unusual hERG Inactivation Gating Mechanism

Abstract

In order to provide some structural insights about the molecular basis of the inactivation gating of the hERG channel, we have reasoned that a chimeric approach in which we recreate the cavity of the hERG chanel in to the KcsA channel could potentially lends a structural framework to begin understand the hERG channel inactivation gating. Recently, we have made an important breakthrough by solving the X-ray structure of the bacterial K+ channel KcsA trapped in the open and C-type inactivated state. These results allowed evaluating the structural changes underlying C-type inactivation gating in K+ channels and it could lend a structural explanation to the unusual C-type inactivation process of the hERG channel. We have used the KcsA channel as a structural scaffold to introduce mutations at positions F103Y, G104A, L105S, V106I and L110V, making KcsA more hERG-like at positions (in hERG) Y652, A653, S654, I655 and V659. Additionally, we have solved the crystal structure of the closed (C) state for this KcsA-Herg chimera and surprisingly the selectivity filter in the closed state is collapsed. We have reasoned that the modifications introduced at the KcsA central cavity have strengthened the allosteric coupling between the activation gate and the selectivity filter, a similar phenomenon could underlies the unusual inactivation gating of the hERG channel. A comprehensive functional study will be presented in addition to a more complete structural analysis.Support: AHA-11SDG5440003 (to LGC).