Cryo-EM Structure of K+-Bound hERG Channel Complexed with the Blocker Astemizole

The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the pharmaceutical industry. The three-dimensional structure of the hERG channel was recently reported at 3.8-Å resolution using cryogenic electron microscopy (cryo-EM). However, the drug inhibition mechanism remains unclear because of the scarce structural information regarding the drug- and potassium-bound hERG channels. In this study, we obtained the cryo-EM density map of potassium-bound hERG channel complexed with astemizole, a well-known hERG inhibitor that increases risk of potentially fatal arrhythmia, at 3.5-Å resolution. The structure suggested that astemizole inhibits potassium conduction by binding directly below the selectivity filter. Furthermore, we propose a possible binding model of astemizole to the hERG channel and provide insights into the unusual sensitivity of hERG to several drugs. [Display omitted] •Cryo-EM structure of hERG channel complexed with astemizole was revealed•Potassium ions were found in the selectivity filter of hERG channel structures•Astemizole inhibits K+ flux by occluding the intracellular pore of selectivity filter•Astemizole has several types of interactions with the binding site Asai et al. determined the cryo-EM structures of the hERG channel in the presence and absence of astemizole, a well-known hERG inhibitor that increases the risk of potentially fatal arrhythmia. The structures propose a possible inhibition model of astemizole to the hERG channel.