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- EMDB-48088: Cryo-EM structure of the mutant KCa2.2_F244S channel -

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Basic information

Entry
Database: EMDB / ID: EMD-48088
TitleCryo-EM structure of the mutant KCa2.2_F244S channel
Map dataEM map of mutant KCa2.2_F244S, missing S3-S4 loop.
Sample
  • Complex: Rat mutant KCa2.2_F244S channel complex with calmodulin in the presence of calcium
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: CALCIUM ION
  • Ligand: water
KeywordsIon channel / Calmodulin binding protein. Membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


Ca2+ activated K+ channels / small conductance calcium-activated potassium channel activity / membrane repolarization during atrial cardiac muscle cell action potential / calcium-activated potassium channel activity / positive regulation of potassium ion transport / inward rectifier potassium channel activity / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / establishment of protein localization to membrane / regulation of potassium ion transmembrane transport ...Ca2+ activated K+ channels / small conductance calcium-activated potassium channel activity / membrane repolarization during atrial cardiac muscle cell action potential / calcium-activated potassium channel activity / positive regulation of potassium ion transport / inward rectifier potassium channel activity / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / establishment of protein localization to membrane / regulation of potassium ion transmembrane transport / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / nitric-oxide synthase binding / regulation of synaptic vesicle exocytosis / calcineurin-mediated signaling / alpha-actinin binding / smooth endoplasmic reticulum / adenylate cyclase binding / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / regulation of neuronal synaptic plasticity / catalytic complex / detection of calcium ion / regulation of synaptic vesicle endocytosis / regulation of cardiac muscle contraction / postsynaptic cytosol / cellular response to interferon-beta / calcium channel inhibitor activity / phosphatidylinositol 3-kinase binding / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / T-tubule / regulation of heart rate / calyx of Held / response to amphetamine / adenylate cyclase activator activity / sarcomere / protein serine/threonine kinase activator activity / nitric-oxide synthase regulator activity / regulation of cytokinesis / spindle microtubule / calcium channel regulator activity / positive regulation of receptor signaling pathway via JAK-STAT / response to calcium ion / sarcolemma / modulation of chemical synaptic transmission / potassium ion transport / cellular response to type II interferon / G2/M transition of mitotic cell cycle / Schaffer collateral - CA1 synapse / Z disc / spindle pole / calcium-dependent protein binding / myelin sheath / growth cone / vesicle / dendritic spine / transmembrane transporter binding / postsynaptic membrane / calmodulin binding / protein domain specific binding / neuronal cell body / calcium ion binding / centrosome / protein kinase binding / glutamatergic synapse / cell surface / protein homodimerization activity / protein-containing complex / mitochondrion / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / : / EF-hand domain pair ...Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Calmodulin-1 / Small conductance calcium-activated potassium channel protein 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsNam YW / Zhang M
Funding support United States, 2 items
OrganizationGrant numberCountry
American Heart Association23AIREA1039423 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS101182-03 United States
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM structures of the small-conductance Ca-activated K2.2 channel.
Authors: Young-Woo Nam / Dohyun Im / Ana Santa Cruz Garcia / Marios L Tringides / Hai Minh Nguyen / Yan Liu / Razan Orfali / Alena Ramanishka / Grigore Pintilie / Chih-Chia Su / Meng Cui / Diomedes E ...Authors: Young-Woo Nam / Dohyun Im / Ana Santa Cruz Garcia / Marios L Tringides / Hai Minh Nguyen / Yan Liu / Razan Orfali / Alena Ramanishka / Grigore Pintilie / Chih-Chia Su / Meng Cui / Diomedes E Logothetis / Edward W Yu / Heike Wulff / K George Chandy / Miao Zhang /
Abstract: Small-conductance Ca-activated K (K2.1-K2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K2.2 channel in complex with calmodulin and Ca, ...Small-conductance Ca-activated K (K2.1-K2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K2.2 channel in complex with calmodulin and Ca, alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy's center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter's GYG signature by 180°, causing the outer selectivity filter to widen and water to enter the filter. Disruption of the tether by a mutation narrows the outer selectivity filter, realigns Tyr362 to the position seen in other K channels, and significantly increases unitary conductance. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of K2.x channels.
History
DepositionNov 26, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateMay 7, 2025-
Current statusMay 7, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48088.png

Downloads & links

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Map

FileDownload / File: emd_48088.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM map of mutant KCa2.2_F244S, missing S3-S4 loop.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.86 Å/pix.
x 512 pix.
= 440.32 Å		0.86 Å/pix.
x 512 pix.
= 440.32 Å		0.86 Å/pix.
x 512 pix.
= 440.32 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 6.5
Minimum - Maximum-90.829920000000001 - 102.681790000000007
Average (Standard dev.)-0.000000000002743 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 440.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: EM half map of mutant KCa2.2 F244S, missing S3-S4 loop.

Fileemd_48088_half_map_1.map
AnnotationEM half map of mutant KCa2.2_F244S, missing S3-S4 loop.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: EM half map of mutant KCa2.2 F244S, missing S3-S4 loop.

Fileemd_48088_half_map_2.map
AnnotationEM half map of mutant KCa2.2_F244S, missing S3-S4 loop.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Rat mutant KCa2.2_F244S channel complex with calmodulin in the pr...

EntireName: Rat mutant KCa2.2_F244S channel complex with calmodulin in the presence of calcium
Components
  • Complex: Rat mutant KCa2.2_F244S channel complex with calmodulin in the presence of calcium
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: CALCIUM ION
  • Ligand: water

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Supramolecule #1: Rat mutant KCa2.2_F244S channel complex with calmodulin in the pr...

SupramoleculeName: Rat mutant KCa2.2_F244S channel complex with calmodulin in the presence of calcium
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 / Details: Mutant KCa2.2_F244S
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 230 KDa

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Macromolecule #1: Small conductance calcium-activated potassium channel protein 2

MacromoleculeName: Small conductance calcium-activated potassium channel protein 2
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 41.114754 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IGYKLGHRRA LFEKRKRLSD YALIFGMFGI VVMVIETELS WGAYDKASLY SLALKCLISL STIILLGLII VYHAREIQLF MVDNGADDW RIAMTYERIF FICLEILVCA IHPIPGNYTF TWTARLAFSY APSTTTADVD IILSIPMFLR LYLIARVMLL H SKLFTDAS ...String:
IGYKLGHRRA LFEKRKRLSD YALIFGMFGI VVMVIETELS WGAYDKASLY SLALKCLISL STIILLGLII VYHAREIQLF MVDNGADDW RIAMTYERIF FICLEILVCA IHPIPGNYTF TWTARLAFSY APSTTTADVD IILSIPMFLR LYLIARVMLL H SKLFTDAS SRSIGALNKI NFNTRFVMKT LMTICPGTVL LVFSISLWII AAWTVRACER YHDQQDVTSN FLGAMWLISI TF LSIGYGD MVPNTYCGKG VCLLTGIMGA GCTALVVAVV ARKLELTKAE KHVHNFMMDT QLTKRVKNAA ANVLRETWLI YKN TKLVKK IDHAKVRKHQ RKFLQAIHQL RSVKMEQRKL NDQAN

UniProtKB: Small conductance calcium-activated potassium channel protein 2

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 16.102626 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QLTEEQIAEF KEAFSLFDKD GDGTITTKEL GTVMRSLGQN PTEAELQDMI NEVDADGNGT IDFPEFLTMM ARKMKDTDSE EEIREAFRV FDKDGNGYIS AAELRHVMTN LGEKLTDEEV DEMIREADID GDGQVNYEEF VQM

UniProtKB: Calmodulin-1

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Macromolecule #3: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

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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

Concentration3 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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: 2.3000000000000003 µm / Nominal defocus min: 1.3 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8v2g

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 81168
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

SoftwareName: UCSF ChimeraX (ver. 1.8)
Output model

PDB-9eio:
Cryo-EM structure of the mutant KCa2.2_F244S channel

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