Cryo-EM Structure of K+-Bound hERG Channel Complexed with the Blocker Astemizole
| Autor: | Toshio Moriya, Shigeru Igaki, Satoshi Ogasawara, Satoshi Yasuda, Tatsuki Asai, Hideyuki Oki, Sisi Chen, Ryohei Ishii, Kazuko Yonemori, Takeshi Murata, Toshiya Senda, Naruhiko Adachi, Masato Kawasaki, Takamitsu Maru, Kano Suzuki |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities 0303 health sciences biology Cryo-electron microscopy Chemistry 030302 biochemistry & molecular biology hERG Cardiac repolarization Potassium channel 03 medical and health sciences Astemizole Structural Biology biology.protein Biophysics medicine Selectivity filter cardiovascular diseases Molecular Biology 030304 developmental biology medicine.drug |
| Zdroj: | Structure. 29:203-212.e4 |
| ISSN: | 0969-2126 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|