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- PDB-7ssv: Structure of human Kv1.3 with Fab-ShK fusion -

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Basic information

Entry
Database: PDB / ID: 7ssv
TitleStructure of human Kv1.3 with Fab-ShK fusion
Components
  • Fab-ShK fusion, heavy chain
  • Fab-ShK fusion, light chain
  • Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
KeywordsIMMUNE SYSTEM / ion channel
Function / homology
Function and homology information


delayed rectifier potassium channel activity / corpus callosum development / voltage-gated monoatomic ion channel activity / Voltage gated Potassium channels / outward rectifier potassium channel activity / optic nerve development / calyx of Held / voltage-gated potassium channel complex / potassium ion transmembrane transport / bioluminescence ...delayed rectifier potassium channel activity / corpus callosum development / voltage-gated monoatomic ion channel activity / Voltage gated Potassium channels / outward rectifier potassium channel activity / optic nerve development / calyx of Held / voltage-gated potassium channel complex / potassium ion transmembrane transport / bioluminescence / generation of precursor metabolites and energy / protein homooligomerization / potassium ion transport / presynaptic membrane / postsynaptic membrane / membrane raft / axon / glutamatergic synapse / 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 / Green fluorescent protein-related ...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 / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / SKP1/BTB/POZ domain superfamily / 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)
unidentified (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.39 Å
AuthorsMeyerson, J.R. / Selvakumar, P. / Smider, V. / Huang, R.
Funding support United States, 1items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
B: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
C: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
D: Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion
H: Fab-ShK fusion, heavy chain
L: Fab-ShK fusion, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)432,1339
Polymers432,0166
Non-polymers1173
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium voltage-gated channel subfamily A member 3,Green fluorescent protein fusion / HGK5 / HLK3 / HPCN3 / Voltage-gated K(+) channel HuKIII / Voltage-gated potassium channel subunit Kv1.3


Mass: 95018.500 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Aequorea victoria (jellyfish)
Gene: KCNA3, HGK5, GFP / Production host: Homo sapiens (human) / References: UniProt: P22001, UniProt: P42212
#2: Antibody Fab-ShK fusion, heavy chain


Mass: 29417.229 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified (others) / Production host: Homo sapiens (human)
#3: Antibody Fab-ShK fusion, light chain


Mass: 22524.752 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified (others) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: Kv1.3 with Fab-ShK / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightUnits: MEGADALTONS
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90267 / Symmetry type: POINT

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