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- EMDB-30413: Cryo-EM structure of K+-bound hERG channel in the presence of ast... -

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Basic information

Entry
Database: EMDB / ID: EMD-30413
TitleCryo-EM structure of K+-bound hERG channel in the presence of astemizole
Map data
Samplepotassium channel:
ligand
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsAsai T / Adachi N / Moriya T / Kawasaki M / Suzuki K / Senda T / Murata T
Funding support Japan, 3 items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP20am0101071 Japan
Japan Society for the Promotion of Science (JSPS)18H05425 Japan
Japan Agency for Medical Research and Development (AMED)JP20am0101083 Japan
CitationJournal: 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 ReportSummary, Full report, XML, About validation report
History
DepositionJul 29, 2020-
Header (metadata) releaseJan 20, 2021-
Map releaseJan 20, 2021-
UpdateJan 20, 2021-
Current statusJan 20, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cn1
  • Surface level: 5.5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7cn1
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30413.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.88 Å/pix.
x 320 pix.
= 282.88 Å
0.88 Å/pix.
x 320 pix.
= 282.88 Å
0.88 Å/pix.
x 320 pix.
= 282.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.884 Å
Density
Contour LevelBy AUTHOR: 5.5 / Movie #1: 5.5
Minimum - Maximum-26.047081 - 37.109512
Average (Standard dev.)-1.8769255e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 282.88 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8840.8840.884
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z282.880282.880282.880
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-26.04737.110-0.000

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Supplemental data

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Sample components

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Entire potassium channel

EntireName: potassium channel / Details: homo-tetramer / Number of components: 3

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Component #1: cellular-component, potassium channel

Cellular-componentName: potassium channel / Details: homo-tetramer / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Vector: BacMam expression vector / Cell of expression system: Expi293F cells

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Component #2: protein, potassium channel

ProteinName: potassium channel / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 91.792086 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: ligand, POTASSIUM ION

LigandName: POTASSIUM IONPotassium / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 3.909805 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 2 mg/mL / pH: 7.4
Support filmThe grid was washed by acetone prior to use.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 291 K / Humidity: 100 % / Details: Blotting time was 5 seconds (blot force 10).

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
ImagingMicroscope: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 120000 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: 800.0 - 2000.0 nm
Specimen HolderModel: OTHER
CameraDetector: FEI FALCON III (4k x 4k)

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Image acquisition

Image acquisitionNumber of digital images: 1865

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 102128
3D reconstructionSoftware: RELION / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement space: REAL
Output model

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