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- EMDB-70275: Cryo-EM structure of KCa3.1/calmodulin channel in complex with NS309 -

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Basic information

Entry
Database: EMDB / ID: EMD-70275
TitleCryo-EM structure of KCa3.1/calmodulin channel in complex with NS309
Map dataCryo-EM map of KCa3.1/calmodulin channel in complex with NS309
Sample
  • Complex: Human Ca3.1/calmodulin channel in complex with NS309
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • 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
KeywordsIon channel / Intermediate conductance calcium-activated potassium channel / Calmodulin binding protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / establishment of protein localization to mitochondrial membrane ...intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / establishment of protein localization to membrane / cell volume homeostasis / phospholipid translocation / 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 / positive regulation of T cell receptor signaling pathway / regulation of synaptic vesicle exocytosis / calcineurin-mediated signaling / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / adenylate cyclase binding / catalytic complex / regulation of synaptic vesicle endocytosis / detection of calcium ion / potassium channel activity / regulation of cardiac muscle contraction / postsynaptic cytosol / cellular response to interferon-beta / calcium channel inhibitor activity / presynaptic cytosol / phosphatidylinositol 3-kinase binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / immune system process / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / response to amphetamine / regulation of heart rate / calyx of Held / nitric-oxide synthase regulator activity / adenylate cyclase activator activity / sarcomere / regulation of cytokinesis / protein serine/threonine kinase activator activity / positive regulation of protein secretion / spindle microtubule / calcium channel regulator activity / positive regulation of receptor signaling pathway via JAK-STAT / establishment of localization in cell / defense response / potassium ion transport / cellular response to type II interferon / Schaffer collateral - CA1 synapse / ruffle membrane / response to calcium ion / spindle pole / G2/M transition of mitotic cell cycle / calcium-dependent protein binding / calcium ion transport / myelin sheath / growth cone / vesicle / protein phosphatase binding / protein homotetramerization / transmembrane transporter binding / neuron projection / calmodulin binding / protein domain specific binding / neuronal cell body / calcium ion binding / centrosome / protein kinase binding / protein homodimerization activity / protein-containing complex / mitochondrion / nucleoplasm / 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
Intermediate conductance calcium-activated potassium channel protein 4 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.59 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 19, 2025-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70275.png

Downloads & links

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Map

FileDownload / File: emd_70275.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of KCa3.1/calmodulin channel in complex with NS309
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.86 Å/pix.
x 500 pix.
= 430. Å		0.86 Å/pix.
x 500 pix.
= 430. Å		0.86 Å/pix.
x 500 pix.
= 430. 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: 6.4
Minimum - Maximum-51.493034000000002 - 65.514719999999997
Average (Standard dev.)0.000000000004996 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 430.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM half map of KCa3.1/calmodulin channel in complex with NS309

Fileemd_70275_half_map_1.map
AnnotationCryo-EM half map of KCa3.1/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 KCa3.1/calmodulin channel in complex with NS309

Fileemd_70275_half_map_2.map
AnnotationCryo-EM half map of KCa3.1/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 : Human Ca3.1/calmodulin channel in complex with NS309

EntireName: Human Ca3.1/calmodulin channel in complex with NS309
Components
  • Complex: Human Ca3.1/calmodulin channel in complex with NS309
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • 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

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Supramolecule #1: Human Ca3.1/calmodulin channel in complex with NS309

SupramoleculeName: Human Ca3.1/calmodulin channel in complex with NS309 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 231.66 KDa

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Macromolecule #1: Intermediate conductance calcium-activated potassium channel protein 4

MacromoleculeName: Intermediate conductance calcium-activated potassium channel protein 4
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.598633 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LGALRRRKRL LEQEKSLAGW ALVLAGTGIG LMVLHAEMLW FGGCSWALYL FLVKCTISIS TFLLLCLIVA FHAKEVQLFM TDNGLRDWR VALTGRQAAQ IVLELVVCGL HPAPVRGPPC VQDLGAPLTS PQPWPGFLGQ GEALLSLAML LRLYLVPRAV L LRSGVLLN ...String:
LGALRRRKRL LEQEKSLAGW ALVLAGTGIG LMVLHAEMLW FGGCSWALYL FLVKCTISIS TFLLLCLIVA FHAKEVQLFM TDNGLRDWR VALTGRQAAQ IVLELVVCGL HPAPVRGPPC VQDLGAPLTS PQPWPGFLGQ GEALLSLAML LRLYLVPRAV L LRSGVLLN ASYRSIGALN QVRFRHWFVA KLYMNTHPGR LLLGLTLGLW LTTAWVLSVA ERQAVNATGH LSDTLWLIPI TF LTIGYGD VVPGTMWGKI VCLCTGVMGV CCTALLVAVV ARKLEFNKAE KHVHNFMMDI QYTKEMKESA ARVLQEAWMF YKH TRRKES HAARRHQRKL LAAINAFRQV RLKHRKLREQ VNSMVDISKM HMILYDLQQN LS

UniProtKB: Intermediate conductance calcium-activated potassium channel protein 4

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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: 16.521094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DQLTEEQIAE FKEAFSLFDK DGDGTITTKE LGTVMRSLGQ NPTEAELQDM INEVDADGNG TIDFPEFLTM MARKMKDTDS EEEIREAFR VFDKDGNGYI SAAELRHVMT NLGEKLTDEE VDEMIREADI DGDGQVNYEE FVQMMTA

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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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: 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:

6cno

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 119846
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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