7CN1

Cryo-EM structure of K+-bound hERG channel in the presence of astemizole

Summary for 7CN1

• Entry DOI: 10.2210/pdb7cn1/pdb
• EMDB information: 30413
• Descriptor: potassium channel, POTASSIUM ION (2 entities in total)
• Functional Keywords: potassium channel, transport protein
• Biological source: Homo sapiens
• Total number of polymer chains: 4
• Total formula weight: 367285.64

Authors

Asai, T.,Adachi, N.,Moriya, T.,Kawasaki, M.,Suzuki, K.,Senda, T.,Murata, T. (deposition date: 2020-07-29, release date: 2021-01-20, Last modification date: 2024-03-27)

Primary citation

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.
Cryo-EM Structure of K + -Bound hERG Channel Complexed with the Blocker Astemizole.
Structure, 29:203-212.e4, 2021

PubMed Abstract: 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.

PubMed: 33450182
DOI: 10.1016/j.str.2020.12.007

Experimental method

ELECTRON MICROSCOPY (3.7 Å)