An Asymmetric C-Type Inactivated Structure of HERG Channel and Its Binding to Chemically Diverse Drugs

Abstract

The fast C-type inactivation displayed by the voltage-activated potassium channel hERG plays a critical role in the repolarization of cardiac cells, and malfunction caused by non-specific binding of drugs or naturally occurring missense mutations affecting inactivation can lead to pathologies. From a pharmacological standpoint, the C-type inactivated state of hERG could bind a large set of chemically diverse drugs. Therefore, understanding the structural basis of C-type inactivation in hERG could help screening compounds for their impact on hERG activity, an indispensable step for drug development. In present study, long-timescale molecular dynamics simulation, free energy landscape calculations, and electrophysiological experiments are combined to address the structural and functional impacts of several disease-associated mutations. Our data suggest that C-type inactivation in hERG is associated with an asymmetrical constricted-like conformation of the selectivity filter, identifying F627 side-chain and the hydrogen bond between Y616 and N627 are key determinants. The energetics of inactivation in hERG, Shaker, and KcsA shows that the C-type inactivation rate depends on the degree of opening of the intracellular gate via the filter-gate allosteric coupling, providing a molecular explanation of the fast inactivation in hERG channel. After the selectivity filter constricts asymmetrically, it is observed that the key residue in the binding site, Y652 in all four subunits, shows high structural flexibility. The snapshots were clustered based on the conformational similarity of Y652, and typical conformations were selected to perform ensemble docking with multiple chemically diverse drugs. The docking results show there are different C-type inactivated conformations more favorable for drugs binding compared with the first experimental conductive structure, demonstrating that the high flexibility of Y652 after constriction is the structural basis for the binding of chemically diverse drug to the hERG channel.