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- EMDB-70207: Cryo-EM structure of KCa2.2/calmodulin channel in complex with NS309 -

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Basic information

Entry
Database: EMDB / ID: EMD-70207
TitleCryo-EM structure of KCa2.2/calmodulin channel in complex with NS309
Map dataCryo-EM map of Kca2.2/calmodulin channel in complex with NS309.
Sample
  • Complex: Rat KCa2.2/calmodulin channel in complex with NS309.
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: (3E)-6,7-dichloro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one
  • Ligand: CALCIUM ION
  • Ligand: water
KeywordsIon channel / Small-conductance calcium-activated potassium channel / 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 / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / positive regulation of potassium ion transport / inward rectifier potassium channel activity / 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 / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / positive regulation of potassium ion transport / inward rectifier potassium channel activity / establishment of protein localization to membrane / regulation of potassium ion transmembrane transport / nitric-oxide synthase binding / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / regulation of synaptic vesicle exocytosis / presynaptic endocytosis / regulation of cardiac muscle cell action potential / negative regulation of ryanodine-sensitive calcium-release channel activity / alpha-actinin binding / calcineurin-mediated signaling / regulation of synaptic vesicle endocytosis / regulation of neuronal synaptic plasticity / protein phosphatase activator activity / postsynaptic cytosol / adenylate cyclase binding / regulation of ryanodine-sensitive calcium-release channel activity / catalytic complex / detection of calcium ion / regulation of cardiac muscle contraction / phosphatidylinositol 3-kinase binding / smooth endoplasmic reticulum / presynaptic cytosol / calcium channel inhibitor activity / cellular response to interferon-beta / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / voltage-gated potassium channel complex / calcium channel regulator activity / potassium ion transmembrane transport / T-tubule / sperm midpiece / calcium channel complex / calyx of Held / nitric-oxide synthase regulator activity / response to amphetamine / adenylate cyclase activator activity / regulation of heart rate / protein serine/threonine kinase activator activity / sarcomere / regulation of cytokinesis / positive regulation of receptor signaling pathway via JAK-STAT / spindle microtubule / modulation of chemical synaptic transmission / potassium ion transport / sarcolemma / Schaffer collateral - CA1 synapse / cellular response to type II interferon / Z disc / response to calcium ion / spindle pole / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / myelin sheath / growth cone / dendritic spine / transmembrane transporter binding / postsynaptic membrane / calmodulin binding / protein domain specific binding / neuronal cell body / centrosome / calcium ion binding / 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: 2.71 Å
AuthorsNam YW / Zhang M
Funding support United States, 4 items
OrganizationGrant numberCountry
American Heart Association23AIREA1039423 United States
American Heart Association24CDA1260237 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)4R33 NS101182-03 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R15 NS130420-01A1 United States
CitationJournal: Res Sq / Year: 2025
Title: Structural basis for the subtype-selectivity of K2.2 channel activators.
Authors: Miao Zhang / Young-Woo Nam / Alena Ramanishka / Yang Xu / Rose Marie Yasuda / Dohyun Im / Meng Cui / George Chandy / Heike Wulff /
Abstract: Small-conductance (K2.2) and intermediate-conductance (K3.1) Ca-activated K channels are gated by a Ca-calmodulin dependent mechanism. NS309 potentiates the activity of both K2.2 and K3.1, while ...Small-conductance (K2.2) and intermediate-conductance (K3.1) Ca-activated K channels are gated by a Ca-calmodulin dependent mechanism. NS309 potentiates the activity of both K2.2 and K3.1, while rimtuzalcap selectively activates K2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of K2.2 channels bound with NS309 and rimtuzalcap, in addition to K3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K2.2. Calmodulin's N-lobes in the K2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin's Nlobes in the K3.1 structure are closer to each other and are constrained by the HC helices of K3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting K2.2 channels.
History
DepositionApr 15, 2025-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70207.png

Downloads & links

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Map

FileDownload / File: emd_70207.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of Kca2.2/calmodulin channel in complex with NS309.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.73 Å/pix.
x 500 pix.
= 364.8 Å		0.73 Å/pix.
x 500 pix.
= 364.8 Å		0.73 Å/pix.
x 500 pix.
= 364.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7296 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.5
Minimum - Maximum-37.547356000000001 - 56.624237000000001
Average (Standard dev.)-0.000000000000536 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 364.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM half map of Kca2.2/calmodulin channel in complex with NS309.

Fileemd_70207_half_map_1.map
AnnotationCryo-EM half map of Kca2.2/calmodulin channel in complex with NS309.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM half map of Kca2.2/calmodulin channel in complex with NS309.

Fileemd_70207_half_map_2.map
AnnotationCryo-EM half map of Kca2.2/calmodulin channel in complex with NS309.
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 KCa2.2/calmodulin channel in complex with NS309.

EntireName: Rat KCa2.2/calmodulin channel in complex with NS309.
Components
  • Complex: Rat KCa2.2/calmodulin channel in complex with NS309.
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: (3E)-6,7-dichloro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one
  • Ligand: CALCIUM ION
  • Ligand: water

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Supramolecule #1: Rat KCa2.2/calmodulin channel in complex with NS309.

SupramoleculeName: Rat KCa2.2/calmodulin channel in complex with NS309. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 229.73 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: 16.406004 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QLTEEQIAEF KEAFSLFDKD GDGTITTKEL GTVMRSLGQN PTEAELQDMI NEVDADGNGT IDFPEFLTMM ARKMKDTDSE EEIREAFRV FDKDGNGYIS AAELRHVMTN LGEKLTDEEV DEMIREADID GDGQVNYEEF VQMMTA

UniProtKB: Calmodulin-1

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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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Macromolecule #4: (3E)-6,7-dichloro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one

MacromoleculeName: (3E)-6,7-dichloro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one
type: ligand / ID: 4 / Number of copies: 4 / Formula: 1KP
Molecular weightTheoretical: 231.036 Da
Chemical component information

ChemComp-1KP:
(3E)-6,7-dichloro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / 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

Concentration2 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 2.2 µm / Nominal defocus min: 0.6 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: 2.71 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139830
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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