7cn1

Publication Abstract from PubMed

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-A 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-A 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.

Cryo-EM Structure of K(+)-Bound hERG Channel Complexed with the Blocker Astemizole.,Asai T, Adachi N, Moriya T, Oki H, Maru T, Kawasaki M, Suzuki K, Chen S, Ishii R, Yonemori K, Igaki S, Yasuda S, Ogasawara S, Senda T, Murata T Structure. 2021 Mar 4;29(3):203-212.e4. doi: 10.1016/j.str.2020.12.007. Epub 2021, Jan 14. PMID:33450182^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.