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- EMDB-18660: Cryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5 -

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Basic information

Entry
Database: EMDB / ID: EMD-18660
TitleCryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5
Map dataSharpened map used for model building and refinement
Sample
  • Complex: Homotetramer of Human Kv3.1a with modulator AUT5
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE
  • Ligand: POTASSIUM ION
  • Ligand: water
KeywordsModulator / Homotetramer / Voltage-gated potassium channel / membrane protein / Kv3.1 / KCNC1
Function / homology
Function and homology information


response to nerve growth factor / globus pallidus development / response to auditory stimulus / response to fibroblast growth factor / response to potassium ion / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels ...response to nerve growth factor / globus pallidus development / response to auditory stimulus / response to fibroblast growth factor / response to potassium ion / corpus callosum development / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels / response to light intensity / optic nerve development / action potential / neuronal cell body membrane / response to amine / kinesin binding / calyx of Held / voltage-gated potassium channel activity / axolemma / voltage-gated potassium channel complex / axon terminus / dendrite membrane / potassium ion transmembrane transport / cerebellum development / protein tetramerization / potassium ion transport / protein homooligomerization / 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
Voltage-gated potassium channel KCNC1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsChi G / Mckinley G / Marsden B / Pike ACW / Ye M / Brooke LM / Bakshi S / Lakshminarayana B / Pilati N / Marasco A ...Chi G / Mckinley G / Marsden B / Pike ACW / Ye M / Brooke LM / Bakshi S / Lakshminarayana B / Pilati N / Marasco A / Gunthorpe M / Alvaro GS / Large CH / Williams E / Sauer DB
Funding support United Kingdom, Switzerland, 2 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Innovative Medicines Initiative Switzerland
CitationJournal: Nat Commun / Year: 2024
Title: The binding and mechanism of a positive allosteric modulator of Kv3 channels.
Authors: Qiansheng Liang / Gamma Chi / Leonardo Cirqueira / Lianteng Zhi / Agostino Marasco / Nadia Pilati / Martin J Gunthorpe / Giuseppe Alvaro / Charles H Large / David B Sauer / Werner Treptow / ...Authors: Qiansheng Liang / Gamma Chi / Leonardo Cirqueira / Lianteng Zhi / Agostino Marasco / Nadia Pilati / Martin J Gunthorpe / Giuseppe Alvaro / Charles H Large / David B Sauer / Werner Treptow / Manuel Covarrubias /
Abstract: Small-molecule modulators of diverse voltage-gated K (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their ...Small-molecule modulators of diverse voltage-gated K (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel's tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.
History
DepositionOct 16, 2023-
Header (metadata) releaseApr 3, 2024-
Map releaseApr 3, 2024-
UpdateApr 3, 2024-
Current statusApr 3, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18660.png

Downloads & links

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Map

FileDownload / File: emd_18660.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map used for model building and refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-2.0746112 - 3.7806542
Average (Standard dev.)0.001067397 (±0.056122925)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18660_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Additional map: Unsharpened map

Fileemd_18660_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Histogram

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Half map: #1

Fileemd_18660_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_18660_half_map_2.map
Projections & Slices
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Sample components

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Entire : Homotetramer of Human Kv3.1a with modulator AUT5

EntireName: Homotetramer of Human Kv3.1a with modulator AUT5
Components
  • Complex: Homotetramer of Human Kv3.1a with modulator AUT5
    • Protein or peptide: Potassium voltage-gated channel subfamily C member 1
  • Ligand: (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE
  • Ligand: POTASSIUM ION
  • Ligand: water

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Supramolecule #1: Homotetramer of Human Kv3.1a with modulator AUT5

SupramoleculeName: Homotetramer of Human Kv3.1a with modulator AUT5 / 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: 58.850078 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGQGDESERI VINVGGTRHQ THRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF ...String:
MGQGDESERI VINVGGTRHQ THRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF WRRWQPRIWA LFEDPYSSRY ARYVAFASLF FILVSITTFC LETHERFNPI VNKTEIENVR NGTQVRYYRE AE TEAFLTY IEGVCVVWFT FEFLMRVIFC PNKVEFIKNS LNIIDFVAIL PFYLEVGLSG LSSKAAKDVL GFLRVVRFVR ILR IFKLTR HFVGLRVLGH TLRASTNEFL LLIIFLALGV LIFATMIYYA ERIGAQPNDP SASEHTHFKN IPIGFWWAVV TMTT LGYGD MYPQTWSGML VGALCALAGV LTIAMPVPVI VNNFGMYYSL AMAKQKLPKK KKKHIPRPPQ LGSPNYCKSV VNSPH HSTQ SDTCPLAQEE ILEINRAGRK PLRGMSIAEN LYFQ

UniProtKB: Voltage-gated potassium channel KCNC1

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Macromolecule #2: (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-ylox...

MacromoleculeName: (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione
type: ligand / ID: 2 / Number of copies: 4 / Formula: WY0
Molecular weightTheoretical: 365.383 Da

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE / type: ligand / ID: 5 / Number of copies: 4 / Formula: PCF
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PCF:
1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE

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Macromolecule #6: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 6 / Number of copies: 6 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 108 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration10 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 17329 / 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: 2.4 µm / Nominal defocus min: 1.0 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: 2975775
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1484211
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7phi


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-8qud:
Cryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5

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