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- PDB-5va3: Cryo-EM structure of the human ether-a-go-go related K+ channel -

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Basic information

Entry
Database: PDB / ID: 5va3
TitleCryo-EM structure of the human ether-a-go-go related K+ channel
ComponentsPotassium voltage-gated channel subfamily H member 2
KeywordsTRANSPORT PROTEIN / K+ channel / PAS / CNBHD / voltage sensor / selectivity filter
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
Model detailstruncation hERGTs
AuthorsWang, W.W. / MacKinnon, R.
Funding support United States, 2items
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, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Data collection / Category: em_software / pdbx_audit_support
Item: _em_software.name / _pdbx_audit_support.funding_organization
Revision 1.2Jul 18, 2018Group: Data collection / Category: em_software / Item: _em_software.name
Revision 1.3Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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  • Biological unit as complete point assembly
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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily H member 2


Theoretical massNumber of molelcules
Total (without water)88,8861
Polymers88,8861
Non-polymers00
Water00
1
A: Potassium voltage-gated channel subfamily H member 2

A: Potassium voltage-gated channel subfamily H member 2

A: Potassium voltage-gated channel subfamily H member 2

A: Potassium voltage-gated channel subfamily H member 2


  • complete point assembly
  • Evidence: gel filtration, The K+ channel is known to form a tetramer and appears so in gel filtration experiments and electron microscopy reconstructions. The provided coordinates contains one ...Evidence: gel filtration, The K+ channel is known to form a tetramer and appears so in gel filtration experiments and electron microscopy reconstructions. The provided coordinates contains one polypeptide of this homotetramer.
  • 356 kDa, 4 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)355,5434
Polymers355,5434
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation3
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit in distinct coordinate
  • point asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: C4 (4 fold cyclic))

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Components

#1: Protein Potassium voltage-gated channel subfamily H member 2 / Eag homolog / Ether-a-go-go-related gene potassium channel 1 / hERG1 / Voltage-gated potassium ...Eag homolog / Ether-a-go-go-related gene potassium channel 1 / hERG1 / Voltage-gated potassium channel subunit Kv11.1


Mass: 88885.664 Da / Num. of mol.: 1 / Fragment: UNP residues 1-140,381-870,1006-1159 / Mutation: S631A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNH2, ERG, ERG1, HERG / Plasmid: BacMam / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q12809

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human ether-a-go-go related K+ channel hERG / Type: ORGANELLE OR CELLULAR COMPONENT
Details: Truncated hERG construct hERGTs (amino acid residues 141-380 and 871-1005 deleted) with S631A mutation
Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTI- / Plasmid: BacMam
Buffer solutionpH: 7.4 / Details: pH 7.4, adjusted with NaOH
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2300 mMpotassium chlorideKCl1
310 mMDithiothreitolC4H10O2S21
40.025 %n-Dodecyl beta-D-maltosideC24H46O111
50.005 %Cholesteryl hemisuccinateC31H50O41
60.025 mg/mLPOPE:POPC:POPA 5:5:11
70.5 mMtris(2-carboxyethyl)phosphineC9H15O6P1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: A 1 mL peak fraction was collected and concentrated ~3x to obtain the final ~6 mg/mL sample.
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 98 % / Chamber temperature: 298 K / Details: one blot: 3 second blot time, 0 blot force

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Calibrated magnification: 38461 X / Nominal defocus max: 3500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 15 sec. / Electron dose: 85 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1505
Details: 50 0.3-second frames were collected for each movie at a dose rate of ~1.8 e-/A2/frame
Image scansWidth: 7420 / Height: 7676 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

EM software
IDNameVersionCategory
1RELION1.4particle selection
2SerialEM3.5image acquisition
3DigitalMicrograph3image acquisition
5RELION1.4CTF correction
6CTFFIND4CTF correction
9UCSF Chimera1.10.2model fitting
10Coot0.8.2model fitting
12RELION1.4initial Euler assignment
13FREALIGN9.11final Euler assignment
14RELION1.4classification
15FREALIGN9.113D reconstruction
16REFMAC5.8model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 333000 / Details: ~333k particles from autopick
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 206 / Algorithm: FOURIER SPACE / Num. of class averages: 4 / Symmetry type: POINT
Atomic model buildingB value: 180 / Protocol: AB INITIO MODEL / Space: RECIPROCAL / Target criteria: Fourier Shell Correlation

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