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- EMDB-25417: Structure of human Kv1.3 with A0194009G09 nanobodies -

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Basic information

Entry
Database: EMDB / ID: EMD-25417
TitleStructure of human Kv1.3 with A0194009G09 nanobodies
Map dataHuman Kv1.3 with nanobody
Sample
  • Complex: Kv1.3 with nanobody A0194009G09
    • Protein or peptide: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
    • Protein or peptide: Nanobody A0194009G09
  • Ligand: POTASSIUM ION
Function / homology
Function and homology information


voltage-gated monoatomic ion channel activity / corpus callosum development / delayed rectifier potassium channel activity / Voltage gated Potassium channels / outward rectifier potassium channel activity / optic nerve development / action potential / calyx of Held / voltage-gated potassium channel activity / voltage-gated potassium channel complex ...voltage-gated monoatomic ion channel activity / corpus callosum development / delayed rectifier potassium channel activity / Voltage gated Potassium channels / outward rectifier potassium channel activity / optic nerve development / action potential / calyx of Held / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / bioluminescence / generation of precursor metabolites and energy / potassium ion transport / protein homooligomerization / presynaptic membrane / postsynaptic membrane / membrane raft / axon / glutamatergic synapse / perinuclear region of cytoplasm / membrane / plasma membrane
Similarity search - Function
Potassium channel, voltage dependent, Kv1.3 / Potassium channel, voltage dependent, Kv1 / 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 / Green fluorescent protein, GFP / SKP1/BTB/POZ domain superfamily ...Potassium channel, voltage dependent, Kv1.3 / Potassium channel, voltage dependent, Kv1 / 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 / Green fluorescent protein, GFP / SKP1/BTB/POZ domain superfamily / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Potassium voltage-gated channel subfamily A member 3 / Green fluorescent protein
Similarity search - Component
Biological speciesHomo sapiens (human) / Aequorea victoria (jellyfish) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsMeyerson JR / Selvakumar P
Funding support United States, 1 items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Nat Commun / Year: 2022
Title: Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.
Authors: Purushotham Selvakumar / Ana I Fernández-Mariño / Nandish Khanra / Changhao He / Alice J Paquette / Bing Wang / Ruiqi Huang / Vaughn V Smider / William J Rice / Kenton J Swartz / Joel R Meyerson /
Abstract: The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block ...The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer's voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.
History
DepositionNov 11, 2021-
Header (metadata) releaseJun 29, 2022-
Map releaseJun 29, 2022-
UpdateJul 20, 2022-
Current statusJul 20, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25417.png

Downloads & links

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Map

FileDownload / File: emd_25417.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman Kv1.3 with nanobody
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 416 pix.
= 354.432 Å		0.85 Å/pix.
x 416 pix.
= 354.432 Å		0.85 Å/pix.
x 416 pix.
= 354.432 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.852 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.591
Minimum - Maximum-2.7612808 - 4.6079507
Average (Standard dev.)0.0027977999 (±0.061915863)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 354.432 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Kv1.3 with nanobody A0194009G09

EntireName: Kv1.3 with nanobody A0194009G09
Components
  • Complex: Kv1.3 with nanobody A0194009G09
    • Protein or peptide: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
    • Protein or peptide: Nanobody A0194009G09
  • Ligand: POTASSIUM ION

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Supramolecule #1: Kv1.3 with nanobody A0194009G09

SupramoleculeName: Kv1.3 with nanobody A0194009G09 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium voltage-gated channel subfamily A member 3,Green fluore...

MacromoleculeName: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Aequorea victoria (jellyfish)
Molecular weightTheoretical: 95.0185 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDERLSLLRS PPPPSARHRA HPPQRPASSG GAHTLVNHGY AEPAAGRELP PDMTVVPGDH LLEPEVADGG GAPPQGGCGG GGCDRYEPL PPSLPAAGEQ DCCGERVVIN ISGLRFETQL KTLCQFPETL LGDPKRRMRY FDPLRNEYFF DRNRPSFDAI L YYYQSGGR ...String:
MDERLSLLRS PPPPSARHRA HPPQRPASSG GAHTLVNHGY AEPAAGRELP PDMTVVPGDH LLEPEVADGG GAPPQGGCGG GGCDRYEPL PPSLPAAGEQ DCCGERVVIN ISGLRFETQL KTLCQFPETL LGDPKRRMRY FDPLRNEYFF DRNRPSFDAI L YYYQSGGR IRRPVNVPID IFSEEIRFYQ LGEEAMEKFR EDEGFLREEE RPLPRRDFQR QVWLLFEYPE SSGPARGIAI VS VLVILIS IVIFCLETLP EFRDEKDYPA STSQDSFEAA GNSTSGSRAG ASSFSDPFFV VETLCIIWFS FELLVRFFAC PSK ATFSRN IMNLIDIVAI IPYFITLGTE LAERQGNGQQ AMSLAILRVI RLVRVFRIFK LSRHSKGLQI LGQTLKASMR ELGL LIFFL FIGVILFSSA VYFAEADDPT SGFSSIPDAF WWAVVTMTTV GYGDMHPVTI GGKIVGSLCA IAGVLTIALP VPVIV SNFN YFYHRETEGE EQSQYMHVGS CQHLSSSAEE LRKARSNSTL SKSEYMVIEE GGMNHSAFPQ TPFKTGNSTA TCTTNN NPN SCVNIKKIFT DVSLEVLFQG PAAAMVSKGE ELFTGVVPIL VELDGDVNGH KFSVSGEGEG DATYGKLTLK LICTTGK LP VPWPTLVTTL GYGLQCFARY PDHMKQHDFF KSAMPEGYVQ ERTIFFKDDG NYKTRAEVKF EGDTLVNRIE LKGIDFKE D GNILGHKLEY NYNSHNVYIT ADKQKNGIKA NFKIRHNIED GGVQLADHYQ QNTPIGDGPV LLPDNHYLSY QSKLSKDPN EKRDHMVLLE FVTAAGITLG MDELYKSAWS HPQFEKGGGS GGGSGGGSWS HPQFEK

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Macromolecule #2: Nanobody A0194009G09

MacromoleculeName: Nanobody A0194009G09 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 13.849449 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MEVQLVESGG GLVQAGGSLG LSCSASGLLF SRNSAGWYRQ APGKQREFVA RIRMGGSINY ADTVKGRFTI SRDNAKNTVY LQMNSLKPE DTAVYYCSSW RTGFYEYWGQ GTLVTVSSAA AHHHHHH

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Macromolecule #3: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 3 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 54.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 123722
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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