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- EMDB-8651: Cryo-EM structure of the human ether-a-go-go related K+ channel -

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Basic information

Entry
Database: EMDB / ID: EMD-8651
TitleCryo-EM structure of the human ether-a-go-go related K+ channel
Map datahERG truncation construct hERGT
Sample
  • Organelle or cellular component: human ether-a-go-go related K+ channel hERG
    • Protein or peptide: Potassium voltage-gated channel subfamily H member 2
KeywordsK+ channel / PAS / CNBHD / voltage sensor / selectivity filter / TRANSPORT PROTEIN
Function / homology
Function and homology information


inward rectifier potassium channel complex / negative regulation of potassium ion export across plasma membrane / regulation of heart rate by hormone / Phase 3 - rapid repolarisation / membrane repolarization during action potential / negative regulation of potassium ion transmembrane transport / membrane repolarization during ventricular cardiac muscle cell action potential / membrane repolarization during cardiac muscle cell action potential / potassium ion export across plasma membrane / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization ...inward rectifier potassium channel complex / negative regulation of potassium ion export across plasma membrane / regulation of heart rate by hormone / Phase 3 - rapid repolarisation / membrane repolarization during action potential / negative regulation of potassium ion transmembrane transport / membrane repolarization during ventricular cardiac muscle cell action potential / membrane repolarization during cardiac muscle cell action potential / potassium ion export across plasma membrane / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of membrane repolarization / membrane repolarization / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels / inward rectifier potassium channel activity / potassium ion homeostasis / ventricular cardiac muscle cell action potential / membrane depolarization during action potential / regulation of ventricular cardiac muscle cell membrane repolarization / regulation of potassium ion transmembrane transport / potassium ion import across plasma membrane / regulation of heart rate by cardiac conduction / voltage-gated potassium channel activity / voltage-gated potassium channel complex / cardiac muscle contraction / potassium ion transmembrane transport / regulation of membrane potential / potassium ion transport / cellular response to xenobiotic stimulus / scaffold protein binding / transcription cis-regulatory region binding / ubiquitin protein ligase binding / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / cell surface / protein homodimerization activity / identical protein binding / plasma membrane
Similarity search - Function
Potassium channel, voltage-dependent, ERG / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / PAS domain / PAS-associated, C-terminal / PAC domain profile. / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain ...Potassium channel, voltage-dependent, ERG / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / PAS domain / PAS-associated, C-terminal / PAC domain profile. / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / PAS repeat profile. / PAS domain / RmlC-like jelly roll fold / PAS domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Voltage-gated inwardly rectifying potassium channel KCNH2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsWang WW / MacKinnon R
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIHGM43949 United States
Howard Hughes Medical Institute (HHMI)R. M. is an investigator in the Howard Hughes Medical Institute United States
CitationJournal: Cell / Year: 2017
Title: Cryo-EM Structure of the Open Human Ether-à-go-go-Related K Channel hERG.
Authors: Weiwei Wang / Roderick MacKinnon /
Abstract: The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or ...The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs. A subtle structural feature of the hERG selectivity filter might correlate with its fast inactivation rate, which is key to hERG's role in cardiac action potential repolarization.
History
DepositionMar 24, 2017-
Header (metadata) releaseMay 3, 2017-
Map releaseMay 3, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.8
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 1.8
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5va2
  • Surface level: 1.8
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8651.png

Downloads & links

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Map

FileDownload / File: emd_8651.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationhERG truncation construct hERGT
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesY (Sec.)X (Row.)Z (Col.)
0.57 Å/pix.
x 256 pix.
= 146.701 Å		0.57 Å/pix.
x 256 pix.
= 146.701 Å		0.47 Å/pix.
x 256 pix.
= 120.1 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX: 0.57305 Å / Y: 0.57305 Å / Z: 0.46914 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.8 / Movie #1: 1.8
Minimum - Maximum-1.8676711 - 6.150801
Average (Standard dev.)0.4355108 (±0.8527215)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin000
Dimensions256256256
Spacing256256256
CellA: 146.7008 Å / B: 146.7008 Å / C: 120.09984 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.573050781250.573050781250.469140625
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z146.701146.701120.100
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S312
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-1.8686.1510.436

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Supplemental data

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Sample components

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Entire : human ether-a-go-go related K+ channel hERG

EntireName: human ether-a-go-go related K+ channel hERG
Components
  • Organelle or cellular component: human ether-a-go-go related K+ channel hERG
    • Protein or peptide: Potassium voltage-gated channel subfamily H member 2

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Supramolecule #1: human ether-a-go-go related K+ channel hERG

SupramoleculeName: human ether-a-go-go related K+ channel hERG / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Truncated hERG construct hERGTs (amino acid residues 141-350 and 871-1005 deleted)
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium voltage-gated channel subfamily H member 2

MacromoleculeName: Potassium voltage-gated channel subfamily H member 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 92.280539 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPVRRGHVAP QNTFLDTIIR KFEGQSRKFI IANARVENCA VIYCNDGFCE LCGYSRAEVM QRPCTCDFLH GPRTQRRAAA QIAQALLGA EERKVEIAFY RKDGSCFLCL VDVVPVKNED GAVIMFILNF EVVMEKDMVG SSPTSDREII APKIKERTHN V TEKVTQVL ...String:
MPVRRGHVAP QNTFLDTIIR KFEGQSRKFI IANARVENCA VIYCNDGFCE LCGYSRAEVM QRPCTCDFLH GPRTQRRAAA QIAQALLGA EERKVEIAFY RKDGSCFLCL VDVVPVKNED GAVIMFILNF EVVMEKDMVG SSPTSDREII APKIKERTHN V TEKVTQVL SLGADVLPEY KLQAPRIHRW TILHYSPFKA VWDWLILLLV IYTAVFTPYS AAFLLKETEE GPPATECGYA CQ PLAVVDL IVDIMFIVDI LINFRTTYVN ANEEVVSHPG RIAVHYFKGW FLIDMVAAIP FDLLIFGSGS EELIGLLKTA RLL RLVRVA RKLDRYSEYG AAVLFLLMCT FALIAHWLAC IWYAIGNMEQ PHMDSRIGWL HNLGDQIGKP YNSSGLGGPS IKDK YVTAL YFTFSSLTSV GFGNVSPNTN SEKIFSICVM LIGSLMYASI FGNVSAIIQR LYSGTARYHT QMLRVREFIR FHQIP NPLR QRLEEYFQHA WSYTNGIDMN AVLKGFPECL QADICLHLNR SLLQHCKPFR GATKGCLRAL AMKFKTTHAP PGDTLV HAG DLLTALYFIS RGSIEILRGD VVVAILGKND IFGEPLNLYA RPGKSNGDVR ALTYCDLHKI HRDDLLEVLD MYPEFSD HF WSSLEITFNL RDTNMIPGGR QYQELPRCPA PTPSLLNIPL SSPGRRPRGD VESRLDALQR QLNRLETRLS ADMATVLQ L LQRQMTLVPP AYSAVTTPGP GPTSTSPLLP VSPLPTLTLD SLSQVSQFMA CEELPPGAPE LPQEGPTRRL SLPGQLGAL TSQPLHRHGS DPGSEASNSL EVLFQ

UniProtKB: Voltage-gated inwardly rectifying potassium channel KCNH2, Voltage-gated inwardly rectifying potassium channel KCNH2, Voltage-gated inwardly rectifying potassium channel KCNH2

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration6 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
300.0 mMKClpotassium chloride
10.0 mMC4H10O2S2Dithiothreitol
0.025 %C24H46O11n-Dodecyl beta-D-maltoside
0.005 %C31H50O4Cholesteryl hemisuccinate
0.025 mg/mLPOPE:POPC:POPA 5:5:1
0.5 mMC9H15O6Ptris(2-carboxyethyl)phosphine

Details: pH 7.4, adjusted with NaOH
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 12 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 98 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: one blot: 3 second blot time, 0 blot force.
DetailsA 1 mL peak fraction was collected and concentrated ~3x to obtain the final ~6 mg/mL sample.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 7420 pixel / Digitization - Dimensions - Height: 7676 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 2443 / Average exposure time: 15.0 sec. / Average electron dose: 85.0 e/Å2
Details: 50 0.3-second frames were collected for each movie at a dose rate of ~1.8 e-/A2/frame
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 38461 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 555000 / Details: ~555000 particles from autopick
Startup modelType of model: INSILICO MODEL / In silico model: hERGTs map was used as initial model
Final reconstructionNumber classes used: 2 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN (ver. 9.11) / Number images used: 144
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: FREALIGN (ver. 9.11)
Final 3D classificationNumber classes: 8 / Avg.num./class: 69375 / Software - Name: RELION (ver. 1.4)

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL / Overall B value: 150 / Target criteria: Fourier Shell Correlation
Output model

PDB-5va2:
Cryo-EM structure of the human ether-a-go-go related K+ channel

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