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- EMDB-9406: TPeA-bound closed MthK channel in nanodisc -

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Basic information

Entry
Database: EMDB / ID: EMD-9406
TitleTPeA-bound closed MthK channel in nanodisc
Map data
Sample
  • Complex: MthK
    • Protein or peptide: Calcium-gated potassium channel MthK
  • Ligand: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
  • Ligand: POTASSIUM IONPotassium
  • Ligand: 1-(tripentyl-$l^{4}-azanyl)pentane
  • Ligand: water
Keywordsion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


monoatomic cation transmembrane transporter activity / potassium ion transport / identical protein binding / metal ion binding / plasma membrane
Similarity search - Function
Regulator of K+ conductance, N-terminal / TrkA-N domain / RCK N-terminal domain profile. / Regulator of K+ conductance, C-terminal / Regulator of K+ conductance, C-terminal domain superfamily / TrkA-C domain / RCK C-terminal domain profile. / Potassium channel domain / Ion channel / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
Calcium-gated potassium channel MthK
Similarity search - Component
Biological speciesMethanothermobacter thermautotrophicus (archaea)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsFan C / Nimigean CM
CitationJournal: Nat Chem Biol / Year: 2024
Title: Calcium-gated potassium channel blockade via membrane-facing fenestrations.
Authors: Chen Fan / Emelie Flood / Nattakan Sukomon / Shubhangi Agarwal / Toby W Allen / Crina M Nimigean /
Abstract: Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because ...Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.
History
DepositionMar 19, 2021-
Header (metadata) releaseSep 21, 2022-
Map releaseSep 21, 2022-
UpdateOct 4, 2023-
Current statusOct 4, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_9406.png

Downloads & links

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Map

FileDownload / File: emd_9406.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.087021485 - 0.15110064
Average (Standard dev.)0.00007065741 (±0.0041843406)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : MthK

EntireName: MthK
Components
  • Complex: MthK
    • Protein or peptide: Calcium-gated potassium channel MthK
  • Ligand: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
  • Ligand: POTASSIUM IONPotassium
  • Ligand: 1-(tripentyl-$l^{4}-azanyl)pentane
  • Ligand: water

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Supramolecule #1: MthK

SupramoleculeName: MthK / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Methanothermobacter thermautotrophicus (archaea)

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Macromolecule #1: Calcium-gated potassium channel MthK

MacromoleculeName: Calcium-gated potassium channel MthK / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Methanothermobacter thermautotrophicus (archaea)
Molecular weightTheoretical: 37.35616 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MVLVIEIIRK HLPRVLKVPA TRILLLVLAV IIYGTAGFHF IEGESWTVSL YWTFVTIATV GYGDYSPSTP LGMYFTVTLI VLGIGTFAV AVERLLEFLI NREQMKLMGL IDVAKSRHVV ICGWSESTLE CLRELRGSEV FVLAEDENVR KKVLRSGANF V HGDPTRVS ...String:
MVLVIEIIRK HLPRVLKVPA TRILLLVLAV IIYGTAGFHF IEGESWTVSL YWTFVTIATV GYGDYSPSTP LGMYFTVTLI VLGIGTFAV AVERLLEFLI NREQMKLMGL IDVAKSRHVV ICGWSESTLE CLRELRGSEV FVLAEDENVR KKVLRSGANF V HGDPTRVS DLEKANVRGA RAVIVDLESD SETIHCILGI RKIDESVRII AEAERYENIE QLRMAGADQV ISPFVISGRL MS RSIDDGY EAMFVQDVLA EESTRRMVEV PIPEGSKLEG VSVLDADIHD VTGVIIIGVG RGDELIIDPP RDYSFRAGDI ILG IGKPEE IERLKNYISA

UniProtKB: Calcium-gated potassium channel MthK

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Macromolecule #2: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]o...

MacromoleculeName: (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate
type: ligand / ID: 2 / Number of copies: 4 / Formula: PGW
Molecular weightTheoretical: 749.007 Da

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Macromolecule #3: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #4: 1-(tripentyl-$l^{4}-azanyl)pentane

MacromoleculeName: 1-(tripentyl-$l^{4}-azanyl)pentane / type: ligand / ID: 4 / Number of copies: 1 / Formula: YQ1
Molecular weightTheoretical: 298.57 Da
Chemical component information

ChemComp-YQ1:
1-(tripentyl-$l^{4}-azanyl)pentane

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / 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

BufferpH: 8.5
VitrificationCryogen name: ETHANE

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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
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 52.23 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80904

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