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- EMDB-28793: Voltage-gated potassium channel Kv3.1 with novel positive modulat... -

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Basic information

Entry
Database: EMDB / ID: EMD-28793
TitleVoltage-gated potassium channel Kv3.1 with novel positive modulator (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one (compound 4)
Map data
Sample
  • Complex: potassium voltage-gated channelVoltage-gated potassium channel
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: ZINC ION
  • Ligand: (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: POTASSIUM IONPotassium
Keywordsion channel / positive modulator / voltage gated / voltage gated potassium channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


response to nerve growth factor / globus pallidus development / response to light intensity / response to potassium ion / response to auditory stimulus / response to fibroblast growth factor / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels ...response to nerve growth factor / globus pallidus development / response to light intensity / response to potassium ion / response to auditory stimulus / response to fibroblast growth factor / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels / delayed rectifier potassium channel activity / optic nerve development / neuronal cell body membrane / voltage-gated potassium channel activity / response to amine / kinesin binding / calyx of Held / axolemma / axon terminus / potassium ion transmembrane transport / voltage-gated potassium channel complex / dendrite membrane / cerebellum development / protein tetramerization / protein homooligomerization / potassium ion transport / response to toxic substance / cellular response to xenobiotic stimulus / presynaptic membrane / postsynaptic membrane / transmembrane transporter binding / cell surface / plasma membrane
Similarity search - Function
Potassium channel, voltage dependent, Kv3.1 / Potassium channel, voltage dependent, Kv3 / Potassium channel, voltage dependent, Kv / Potassium channel tetramerisation-type BTB domain / BTB/POZ domain / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / Voltage-dependent channel domain superfamily / SKP1/BTB/POZ domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Potassium voltage-gated channel subfamily C member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsChen Y / Ishchenko A
Funding support United States, 1 items
OrganizationGrant numberCountry
Merck & Co. United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.
Authors: Yun-Ting Chen / Mee Ra Hong / Xin-Jun Zhang / James Kostas / Yuxing Li / Richard L Kraus / Vincent P Santarelli / Deping Wang / Yacob Gomez-Llorente / Alexei Brooun / Corey Strickland / ...Authors: Yun-Ting Chen / Mee Ra Hong / Xin-Jun Zhang / James Kostas / Yuxing Li / Richard L Kraus / Vincent P Santarelli / Deping Wang / Yacob Gomez-Llorente / Alexei Brooun / Corey Strickland / Stephen M Soisson / Daniel J Klein / Anthony T Ginnetti / Michael J Marino / Shawn J Stachel / Andrii Ishchenko /
Abstract: Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K) to diffuse across a hydrophobic cell membrane. These unique ...Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.
History
DepositionNov 4, 2022-
Header (metadata) releaseOct 25, 2023-
Map releaseOct 25, 2023-
UpdateOct 25, 2023-
Current statusOct 25, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28793.png

Downloads & links

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Map

FileDownload / File: emd_28793.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.84 Å
Density
Contour LevelBy AUTHOR: 0.21
Minimum - Maximum-1.2360415 - 1.7139502
Average (Standard dev.)0.010962389 (±0.045140997)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 241.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_28793_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_28793_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : potassium voltage-gated channel

EntireName: potassium voltage-gated channelVoltage-gated potassium channel
Components
  • Complex: potassium voltage-gated channelVoltage-gated potassium channel
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: ZINC ION
  • Ligand: (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: POTASSIUM IONPotassium

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Supramolecule #1: potassium voltage-gated channel

SupramoleculeName: potassium voltage-gated channel / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 240 KDa

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Macromolecule #1: Potassium voltage-gated channel subfamily C member 1

MacromoleculeName: Potassium voltage-gated channel subfamily C member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.745266 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDHDGD YKDHDIDYKD DDDKLEVLFQ GPGSMGQGDE SERIVINVGG TRHQTYRSTL RTLPGTRLAW LAEPDAHSHF DYDPRADEF FFDRHPGVFA HILNYYRTGK LHCPADVCGP LYEEELAFWG IDETDVEPCC WMTYRQHRDA EEALDSFGGA P LDNSADDA ...String:
MADYKDHDGD YKDHDIDYKD DDDKLEVLFQ GPGSMGQGDE SERIVINVGG TRHQTYRSTL RTLPGTRLAW LAEPDAHSHF DYDPRADEF FFDRHPGVFA HILNYYRTGK LHCPADVCGP LYEEELAFWG IDETDVEPCC WMTYRQHRDA EEALDSFGGA P LDNSADDA DADGPGDSGD GEDELEMTKR LALSDSPDGR PGGFWRRWQP RIWALFEDPY SSRYARYVAF ASLFFILVSI TT FCLETHE RFNPIVNKTE IENVRNGTQV RYYREAETEA FLTYIEGVCV VWFTFEFLMR VIFCPNKVEF IKNSLNIIDF VAI LPFYLE VGLSGLSSKA AKDVLGFLRV VRFVRILRIF KLTRHFVGLR VLGHTLRAST NEFLLLIIFL ALGVLIFATM IYYA ERIGA QPNDPSASEH THFKNIPIGF WWAVVTMTTL GYGDMYPQTW SGMLVGALCA LAGVLTIAMP VPVIVNNFGM YYSLA MAKQ KLPKKKKKHI PRPPQLGSPN YCKSVVNSPH HSTQSDTCPL AQEEILEINR AGRKPLRGMS ILEVLFQG

UniProtKB: Potassium voltage-gated channel subfamily C member 1

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)o...

MacromoleculeName: (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one
type: ligand / ID: 3 / Number of copies: 4 / Formula: X9T
Molecular weightTheoretical: 437.879 Da
Chemical component information

ChemComp-X9T:
(9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one

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Macromolecule #4: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 4 / Number of copies: 4 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

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Macromolecule #5: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 5 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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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

Concentration3.2 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 42.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1883143
Startup modelType of model: OTHER / Details: ab-initio model from cryoSPARC
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 125905

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8f1c:
Voltage-gated potassium channel Kv3.1 with novel positive modulator (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one (compound 4)

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