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- PDB-8zyq: Cryo-EM Structure of pimozide-bound hERG Channel -

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Basic information

Entry
Database: PDB / ID: 8zyq
TitleCryo-EM Structure of pimozide-bound hERG Channel
ComponentsPotassium voltage-gated channel subfamily H member 2
KeywordsTRANSPORT PROTEIN / drug toxicity / potassium ion / hERG / cryo-EM / 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 / membrane depolarization during action potential / 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 / 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
Chem-1II / Voltage-gated inwardly rectifying potassium channel KCNH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsMiyashita, Y. / Moriya, T. / Kato, T. / Kawasaki, M. / Yasuda, Y. / Adachi, N. / Suzuki, K. / Ogasawara, S. / Saito, T. / Senda, T. / Murata, T.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED) Japan
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: Structure / Year: 2024
Title: Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors.
Authors: Yasuomi Miyashita / Toshio Moriya / Takafumi Kato / Masato Kawasaki / Satoshi Yasuda / Naruhiko Adachi / Kano Suzuki / Satoshi Ogasawara / Tetsuichiro Saito / Toshiya Senda / Takeshi Murata /
Abstract: During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a ...During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.
History
DepositionJun 18, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily H member 2
B: Potassium voltage-gated channel subfamily H member 2
C: Potassium voltage-gated channel subfamily H member 2
D: Potassium voltage-gated channel subfamily H member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)367,6305
Polymers367,1684
Non-polymers4621
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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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 / ERG-1 / Eag-related protein 1 / ...Eag homolog / Ether-a-go-go-related gene potassium channel 1 / ERG-1 / Eag-related protein 1 / Ether-a-go-go-related protein 1 / H-ERG / hERG-1 / hERG1 / Voltage-gated potassium channel subunit Kv11.1


Mass: 91792.086 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNH2, ERG, ERG1, HERG / Production host: Homo sapiens (human) / References: UniProt: Q12809
#2: Chemical ChemComp-1II / 3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one


Mass: 461.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29F2N3O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: potassium channel / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98139 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 81.42 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00376485
ELECTRON MICROSCOPYf_angle_d0.558798
ELECTRON MICROSCOPYf_chiral_restr0.03761033
ELECTRON MICROSCOPYf_plane_restr0.00371033
ELECTRON MICROSCOPYf_dihedral_angle_d15.6142219

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