|Entry||Database: EMDB / ID: EMD-30413|
|Title||Cryo-EM structure of K+-bound hERG channel in the presence of astemizole|
|Biological species||Homo sapiens (human)|
|Method||single particle reconstruction / cryo EM / Resolution: 3.7 Å|
|Authors||Asai T / Adachi N / Moriya T / Kawasaki M / Suzuki K / Senda T / Murata T|
|Funding support|| Japan, 3 items |
|Citation||Journal: Structure / Year: 2020|
Title: Cryo-EM structure of K-bound hERG channel complexed with the blocker astemizole.
Authors: Tatsuki Asai / Naruhiko Adachi / Toshio Moriya / Hideyuki Oki / Takamitsu Maru / Masato Kawasaki / Kano Suzuki / Sisi Chen / Ryohei Ishii / Kazuko Yonemori / Shigeru Igaki / Satoshi Yasuda / ...Authors: Tatsuki Asai / Naruhiko Adachi / Toshio Moriya / Hideyuki Oki / Takamitsu Maru / Masato Kawasaki / Kano Suzuki / Sisi Chen / Ryohei Ishii / Kazuko Yonemori / Shigeru Igaki / Satoshi Yasuda / Satoshi Ogasawara / Toshiya Senda / Takeshi Murata /
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- ...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.
|Validation Report||Summary, Full report, XML, About validation report|
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_30413.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 0.884 Å|
|Symmetry||Space group: 1|
CCP4 map header:
-Entire potassium channel
|Entire||Name: potassium channel / Details: homo-tetramer / Number of components: 3|
-Component #1: cellular-component, potassium channel
|Cellular-component||Name: potassium channel / Details: homo-tetramer / Recombinant expression: No|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human) / Vector: BacMam expression vector / Cell of expression system: Expi293F cells|
-Component #2: protein, potassium channel
|Protein||Name: potassium channel / Number of Copies: 4 / Recombinant expression: No|
|Mass||Theoretical: 91.792086 kDa|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #3: ligand, POTASSIUM ION
|Ligand||Name: POTASSIUM IONPotassium / Number of Copies: 3 / Recombinant expression: No|
|Mass||Theoretical: 3.909805 MDa|
|Specimen||Specimen state: Particle / Method: cryo EM|
|Sample solution||Specimen conc.: 2 mg/mL / pH: 7.4|
|Support film||The grid was washed by acetone prior to use.|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 291 K / Humidity: 100 % / Details: Blotting time was 5 seconds (blot force 10).|
-Electron microscopy imaging
Model: Talos Arctica / Image courtesy: FEI Company
|Imaging||Microscope: FEI TALOS ARCTICA|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Magnification: 120000 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: 800.0 - 2000.0 nm|
|Specimen Holder||Model: OTHER|
|Camera||Detector: FEI FALCON III (4k x 4k)|
|Image acquisition||Number of digital images: 1865|
|Processing||Method: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 102128|
|3D reconstruction||Software: RELION / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF|
|FSC plot (resolution estimation)|
-Atomic model buiding
|Modeling #1||Refinement space: REAL|
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