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- EMDB-45599: Cryo-EM structure of the human ether-a-go-go related K+ channel (... -

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Basic information

Entry
Database: EMDB / ID: EMD-45599
TitleCryo-EM structure of the human ether-a-go-go related K+ channel (hERG) in 300 mM K+ without symmetry
Map data
Sample
  • Complex: hERG channel tetramer
    • Protein or peptide: Potassium voltage-gated channel subfamily H member 2
KeywordsIon channel / MEMBRANE 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: 3.5 Å
AuthorsLau CHY / Hunter MJ / Vandenberg JI
Funding support Australia, 2 items
OrganizationGrant numberCountry
Australian Research Council (ARC) Australia
National Health and Medical Research Council (NHMRC, Australia) Australia
CitationJournal: Nat Commun / Year: 2024
Title: Potassium dependent structural changes in the selectivity filter of HERG potassium channels.
Authors: Carus H Y Lau / Emelie Flood / Mark J Hunter / Billy J Williams-Noonan / Karen M Corbett / Chai-Ann Ng / James C Bouwer / Alastair G Stewart / Eduardo Perozo / Toby W Allen / Jamie I Vandenberg /
Abstract: The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go ...The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG.
History
DepositionJul 1, 2024-
Header (metadata) releaseAug 21, 2024-
Map releaseAug 21, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45599.png

Downloads & links

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Map

FileDownload / File: emd_45599.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 300 pix.
= 315. Å		1.05 Å/pix.
x 300 pix.
= 315. Å		1.05 Å/pix.
x 300 pix.
= 315. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0135
Minimum - Maximum-0.09435302 - 0.16464138
Average (Standard dev.)0.00005961357 (±0.0033724979)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 315.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45599_msk_1.map
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Half map: #1

Fileemd_45599_half_map_1.map
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Half map: #2

Fileemd_45599_half_map_2.map
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Sample components

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Entire : hERG channel tetramer

EntireName: hERG channel tetramer
Components
  • Complex: hERG channel tetramer
    • Protein or peptide: Potassium voltage-gated channel subfamily H member 2

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Supramolecule #1: hERG channel tetramer

SupramoleculeName: hERG channel tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.683352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPVRRGHVAP QNTFLDTIIR KFEGQSRKFI IANARVENCA VIYCNDGFCE LCGYSRAEVM QRPCTCDFLH GPRTQRRAAA QIAQALLGA EERKVEIAFY RKDGSCFLCL VDVVPVKNED GAVIMFILNF EVVMEKDMVG SGADVLPEYK LQAPRIHRWT I LHYSPFKA ...String:
MPVRRGHVAP QNTFLDTIIR KFEGQSRKFI IANARVENCA VIYCNDGFCE LCGYSRAEVM QRPCTCDFLH GPRTQRRAAA QIAQALLGA EERKVEIAFY RKDGSCFLCL VDVVPVKNED GAVIMFILNF EVVMEKDMVG SGADVLPEYK LQAPRIHRWT I LHYSPFKA VWDWLILLLV IYTAVFTPYS AAFLLKETEE GPPATECGYA CQPLAVVDLI VDIMFIVDIL INFRTTYVNA NE EVVSHPG RIAVHYFKGW FLIDMVAAIP FDLLIFGSGS EELIGLLKTA RLLRLVRVAR KLDRYSEYGA AVLFLLMCTF ALI AHWLAC IWYAIGNMEQ PHMDSRIGWL HNLGDQIGKP YNSSGLGGPS IKDKYVTALY FTFSSLTSVG FGNVSPNTNS EKIF SICVM LIGSLMYASI FGNVSAIIQR LYSGTARYHT QMLRVREFIR FHQIPNPLRQ RLEEYFQHAW SYTNGIDMNA VLKGF PECL QADICLHLNR SLLQHCKPFR GATKGCLRAL AMKFKTTHAP PGDTLVHAGD LLTALYFISR GSIEILRGDV VVAILG KND IFGEPLNLYA RPGKSNGDVR ALTYCDLHKI HRDDLLEVLD MYPEFSDHFW SSLEITFNLR DTNMIPGGRQ YQELPRC PA PTPSLLNIPL SSPGRRPRGD VESRLDALQR QLNRLETRLS ADMATVLQLL QRQMTLVPPA YSAVTTPGPG PTSTSPLL P VSPLPTLTLD SLSQVSQFMA CEELPPGAPE LPQEGPTRRL SLPGQLGALT SQPLHRHGSD PGS

UniProtKB: 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

Concentration7.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
300.0 mMPotassium chloride
20.0 mMHEPES pH 7.4
10.0 mMDTT
0.025 %DDM
0.005 %CHS
0.0114 mg/mlPOPC
0.0114 mg/mlPOPE
0.0022 mg/mlPOPA
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER / Pretreatment - Pressure: 0.05 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 884778
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 232371
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final 3D classificationNumber classes: 6
FSC plot (resolution estimation)

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