|Entry||Database: PDB / ID: 7cn0|
|Title||Cryo-EM structure of K+-bound hERG channel|
|Components||potassium channel 1|
|Keywords||TRANSPORT PROTEIN / potassium channel|
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å|
|Authors||Asai, T. / Adachi, N. / Moriya, T. / Kawasaki, M. / Suzuki, K. / Senda, T. / Murata, T.|
|Funding support|| Japan, 3items |
|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.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
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A: potassium channel 1
B: potassium channel 1
C: potassium channel 1
D: potassium channel 1
Mass: 91792.086 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: BacMam expression vector / Production host: Homo sapiens (human) / Strain (production host): Expi293F cells
Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: potassium channel / Type: ORGANELLE OR CELLULAR COMPONENT / Details: homo-tetramer / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Homo sapiens (human) / Cell: Expi293F cells / Plasmid: BacMam expression vector|
|Buffer solution||pH: 7.4|
|Specimen||Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was mono-disperse.|
|Specimen support||Details: The grid was washed by acetone prior to use. / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K / Details: Blotting time was 5 seconds (blot force 10)|
-Electron microscopy imaging
Model: Talos Arctica / Image courtesy: FEI Company
|Microscopy||Model: FEI TALOS ARCTICA|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 120000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm|
|Specimen holder||Cryogen: NITROGEN|
|Image recording||Average exposure time: 56.13 sec. / Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1496|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Particle selection||Num. of particles selected: 999720|
|Symmetry||Point symmetry: C4 (4 fold cyclic)|
|3D reconstruction||Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173770 / Symmetry type: POINT|
|Atomic model building||Protocol: AB INITIO MODEL / Space: REAL|
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