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- EMDB-44978: Structure of human k2P13.1 (THIK-1) S136P Y273A in lipid nanodisc -

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Basic information

Entry
Database: EMDB / ID: EMD-44978
TitleStructure of human k2P13.1 (THIK-1) S136P Y273A in lipid nanodisc
Map data
Sample
  • Complex: Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc
    • Protein or peptide: Potassium channel subfamily K member 13
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: N-OCTANE
  • Ligand: HEXANE
  • Ligand: LINOLEIC ACID
  • Ligand: POTASSIUM ION
Keywordsion channel / k2p channel / membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


regulation of excitatory synapse pruning / Tandem pore domain halothane-inhibited K+ channel (THIK) / regulation of NLRP3 inflammasome complex assembly / Phase 4 - resting membrane potential / potassium ion leak channel activity / regulation of resting membrane potential / outward rectifier potassium channel activity / monoatomic ion channel complex / potassium channel activity / potassium ion transmembrane transport ...regulation of excitatory synapse pruning / Tandem pore domain halothane-inhibited K+ channel (THIK) / regulation of NLRP3 inflammasome complex assembly / Phase 4 - resting membrane potential / potassium ion leak channel activity / regulation of resting membrane potential / outward rectifier potassium channel activity / monoatomic ion channel complex / potassium channel activity / potassium ion transmembrane transport / protein heterodimerization activity / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
Two pore domain potassium channel, THIK / Two pore domain potassium channel / Potassium channel domain / Ion channel
Similarity search - Domain/homology
Potassium channel subfamily K member 13
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.39 Å
AuthorsRoy-Chowdhury S / Minor DL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)R01 MH093603 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structure of the human K13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site.
Authors: Shatabdi Roy-Chowdhury / Seil Jang / Fayal Abderemane-Ali / Fiona Naughton / Michael Grabe / Daniel L Minor /
Abstract: Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly ...Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1-M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, K7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1-M4 interface for K control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.
History
DepositionMay 21, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44978.png

Downloads & links

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Map

FileDownload / File: emd_44978.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 288 pix.
= 240.48 Å		0.84 Å/pix.
x 288 pix.
= 240.48 Å		0.84 Å/pix.
x 288 pix.
= 240.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.111
Minimum - Maximum-0.24491999 - 0.5535417
Average (Standard dev.)-0.0007413235 (±0.0141863385)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 240.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44978_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_44978_half_map_2.map
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Sample components

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Entire : Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc

EntireName: Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc
Components
  • Complex: Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc
    • Protein or peptide: Potassium channel subfamily K member 13
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: N-OCTANE
  • Ligand: HEXANE
  • Ligand: LINOLEIC ACID
  • Ligand: POTASSIUM ION

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Supramolecule #1: Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc

SupramoleculeName: Human K2P13.1 with S136P and Y273A muatations in lipid nanodisc
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium channel subfamily K member 13

MacromoleculeName: Potassium channel subfamily K member 13 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.29152 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGRGFSWGP GHLNEDNARF LLLAALIVLY LLGGAAVFSA LELAHERQAK QRWEERLAQF SRGHQLSRDE LRGFLRHYEE ATRAGIRVD NVRPRWDFTG AFYFVGTVVS TIGFGMTTPA TVGGKIFLIF YGLVGCPSTI LFFNLFLERL ITIIAYIMKS C HQRQLRRR ...String:
MAGRGFSWGP GHLNEDNARF LLLAALIVLY LLGGAAVFSA LELAHERQAK QRWEERLAQF SRGHQLSRDE LRGFLRHYEE ATRAGIRVD NVRPRWDFTG AFYFVGTVVS TIGFGMTTPA TVGGKIFLIF YGLVGCPSTI LFFNLFLERL ITIIAYIMKS C HQRQLRRR GALPQESLKD AGQCEVDSLA GWKPSVYYVM LILCTASILI SCCASAMYTP IEGWSYFDSL YFCFVAFSTI GF GDLVSSQ NAHYESQGLY RFANFVFILM GVCCIASLFN VISILIKQSL NWILRKMDSG CCPQCQRGLL RSRRNVVMPG SVR NRCNIS IETDGVAESD TDGRRLSGEM ISMK

UniProtKB: Potassium channel subfamily K member 13

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Macromolecule #2: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 2 / Number of copies: 2 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #3: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 3 / Number of copies: 4 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #4: N-OCTANE

MacromoleculeName: N-OCTANE / type: ligand / ID: 4 / Number of copies: 8 / Formula: OCT
Molecular weightTheoretical: 114.229 Da
Chemical component information

ChemComp-OCT:
N-OCTANE

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Macromolecule #5: HEXANE

MacromoleculeName: HEXANE / type: ligand / ID: 5 / Number of copies: 2 / Formula: HEX
Molecular weightTheoretical: 86.175 Da
Chemical component information

ChemComp-HEX:
HEXANE

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Macromolecule #6: LINOLEIC ACID

MacromoleculeName: LINOLEIC ACID / type: ligand / ID: 6 / Number of copies: 2 / Formula: EIC
Molecular weightTheoretical: 280.445 Da
Chemical component information

ChemComp-EIC:
LINOLEIC ACID

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Macromolecule #7: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 7 / 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

Concentration1 mg/mL
BufferpH: 7.8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Detailsmutant protein in lipid nanodisc

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 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

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.39 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 493313
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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