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- EMDB-70240: Cryo-EM structure of KCa2.2_II/calmodulin channel in complex with... -

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Entry
Database: EMDB / ID: EMD-70240
TitleCryo-EM structure of KCa2.2_II/calmodulin channel in complex with rimtuzalcap
Map dataCryo-EM map of KCa2.2_II/calmodulin channel in complex with rimtuzalcap
Sample
  • Complex: RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(morpholin-4-yl)pyrimidin-4-amine
  • Ligand: water
KeywordsIon channel / Small-conductance calcium-activated potassium channel / 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 / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / adenylate cyclase binding / catalytic complex / regulation of neuronal synaptic plasticity / regulation of synaptic vesicle endocytosis / detection of calcium ion / regulation of cardiac muscle contraction / postsynaptic cytosol / smooth endoplasmic reticulum / 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 / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / T-tubule / 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 / spindle microtubule / calcium channel regulator activity / positive regulation of receptor signaling pathway via JAK-STAT / sarcolemma / modulation of chemical synaptic transmission / potassium ion transport / cellular response to type II interferon / Schaffer collateral - CA1 synapse / Z disc / response to calcium ion / spindle pole / G2/M transition of mitotic cell cycle / 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 speciesHomo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.96 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 17, 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_70240.png

Downloads & links

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Map

FileDownload / File: emd_70240.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of KCa2.2_II/calmodulin channel in complex with rimtuzalcap
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: 6.5
Minimum - Maximum-45.961562999999998 - 74.862755000000007
Average (Standard dev.)0.00000000000172 (±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 KCa2.2 II/calmodulin channel in complex...

Fileemd_70240_half_map_1.map
AnnotationCryo-EM half map of KCa2.2_II/calmodulin channel in complex with rimtuzalcap
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 II/calmodulin channel in complex...

Fileemd_70240_half_map_2.map
AnnotationCryo-EM half map of KCa2.2_II/calmodulin channel in complex with rimtuzalcap
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap

EntireName: RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap
Components
  • Complex: RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap
    • Protein or peptide: Small conductance calcium-activated potassium channel protein 2
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(morpholin-4-yl)pyrimidin-4-amine
  • Ligand: water

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Supramolecule #1: RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap

SupramoleculeName: RatKCa2.2_II/calmodulin channel in complex with rimtuzalcap
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
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: 43.349289 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KLGHRRALFE KRKRLSDYAL IFGMFGIVVM VIETELSWGA YDKASLYSLA LKCLISLSTI ILLGLIIVYH AREIQLFMVD NGADDWRIA MTYERIFFIC LEILVCAIHP IPGNYTFTWT ARLAFSYAPS TTTADVDIIL SIPMFLRLYL IARVMLLHSK L FTDASSRS ...String:
KLGHRRALFE KRKRLSDYAL IFGMFGIVVM VIETELSWGA YDKASLYSLA LKCLISLSTI ILLGLIIVYH AREIQLFMVD NGADDWRIA MTYERIFFIC LEILVCAIHP IPGNYTFTWT ARLAFSYAPS TTTADVDIIL SIPMFLRLYL IARVMLLHSK L FTDASSRS IGALNKINFN TRFVMKTLMT ICPGTVLLVF SISLWIIAAW TVRACERYHD QQDVTSNFLG AMWLISITFL SI GYGDMVP NTYCGKGVCL LTGIMGAGCT ALVVAVVARK LELTKAEKHV HNFMMDTQLT KRVKNAAANV LRETWLIYKN TKL VKKIDH AKVRKHQRKF LQAIHQLRSV KMEQRKLNDQ ANTLVDLAKT QNIMYDMISD LNER

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: 16.277873 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
LTEEQIAEFK EAFSLFDKDG DGTITTKELG TVMRSLGQNP TEAELQDMIN EVDADGNGTI DFPEFLTMMA RKMKDTDSEE EIREAFRVF DKDGNGYISA AELRHVMTNL GEKLTDEEVD EMIREADIDG DGQVNYEEFV QMMTA

UniProtKB: Calmodulin-1

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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: N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(morpho...

MacromoleculeName: N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(morpholin-4-yl)pyrimidin-4-amine
type: ligand / ID: 4 / Number of copies: 4 / Formula: A1B92
Molecular weightTheoretical: 378.42 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

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: 2.3000000000000003 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: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 102190
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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