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- EMDB-74625: Cryo-EM structure of KCa3.1_I/calmodulin channel in complex with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-74625
TitleCryo-EM structure of KCa3.1_I/calmodulin channel in complex with SKA111.
Map dataCryo-EM map of KCa3.1_I/calmodulin channel in complex with SKA111.
Sample
  • Complex: Human KCa3.1_I/calmodulin channel in complex with SKA111.
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: 5-methylnaphtho[1,2-d][1,3]thiazol-2-amine
  • Ligand: POTASSIUM ION
  • Ligand: CALCIUM ION
KeywordsIntermediate conductance calcium-activated potassium channel / Ion channel / Calmodulin binding protein / TRANSPORT PROTEIN / MEMBRANE PROTEIN
Function / homology
Function and homology information


intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / stabilization of membrane potential / Ca2+ activated K+ channels / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / positive regulation of T cell receptor signaling pathway ...intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / stabilization of membrane potential / Ca2+ activated K+ channels / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / positive regulation of T cell receptor signaling pathway / cell volume homeostasis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / phospholipid translocation / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of high voltage-gated calcium channel activity / PKA activation / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / : / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / regulation of cell communication by electrical coupling involved in cardiac conduction / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / potassium channel activity / detection of calcium ion / immune system process / regulation of cardiac muscle contraction / catalytic complex / RHO GTPases activate IQGAPs / calcium channel inhibitor activity / presynaptic cytosol / Activation of AMPK downstream of NMDARs / cellular response to interferon-beta / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / eNOS activation / Protein methylation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / FCERI mediated Ca+2 mobilization / calcium channel complex / potassium ion transmembrane transport / substantia nigra development / FCGR3A-mediated IL10 synthesis / regulation of heart rate / establishment of localization in cell / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Ras activation upon Ca2+ influx through NMDA receptor / calyx of Held / adenylate cyclase activator activity / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / regulation of cytokinesis / protein serine/threonine kinase activator activity / spindle microtubule / positive regulation of protein secretion / sarcomere / positive regulation of receptor signaling pathway via JAK-STAT / Translocation of SLC2A4 (GLUT4) to the plasma membrane / calcium channel regulator activity / potassium ion transport / defense response / Transcriptional activation of mitochondrial biogenesis / RAF activation / response to calcium ion / cellular response to type II interferon / G2/M transition of mitotic cell cycle / Stimuli-sensing channels / ruffle membrane / spindle pole
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsNam YW / Ramanishka A / 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: Structure / Year: 2026
Title: Structural basis for the subtype-selective activation of K3.1 channels.
Authors: Alena Ramanishka / Joshua A Nasburg / Yang Xu / Xinyi Ma / Reza Mehvar / Meng Cui / Young-Woo Nam / Heike Wulff / Miao Zhang /
Abstract: The intermediate-conductance (K3.1) and the small-conductance (K2.2) Ca-activated K channels share a Ca-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K3.1 ...The intermediate-conductance (K3.1) and the small-conductance (K2.2) Ca-activated K channels share a Ca-calmodulin dependent gating mechanism. We report cryo-electron microscopy structures of K3.1 and K2.2 in complex with two benzothiazole-type activators. While SKA-31 is only moderately selective (∼7.3-fold), its derivative SKA-111 exhibits ∼70-fold selectivity for K3.1 over K2.2. SKA-31 and SKA-111 both bind in a pocket at the interface between the SA helix and calmodulin where they allosterically modulate the inner gate of the two channels. SKA-31 binds with comparable energies in the two channels, consistent with its moderate selectivity for K3.1 over K2.2. In the K3.1 structure, the calmodulin helix IV is positioned outward, forming a pocket that more readily accommodates the bulkier SKA-111 that sits deeper inside calmodulin's N-lobe in K3.1 than in K2.2. The resulting higher binding energy explains the improved selectivity of SKA-111 for K3.1 compared to the less selective SKA-31.
History
DepositionDec 20, 2025-
Header (metadata) releaseJan 14, 2026-
Map releaseJan 14, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74625.png

Downloads & links

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Map

FileDownload / File: emd_74625.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of KCa3.1_I/calmodulin channel in complex with SKA111.
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 6.0
Minimum - Maximum-31.220286999999999 - 68.054490000000001
Average (Standard dev.)0.000000000000737 (±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 I/calmodulin channel in complex...

Fileemd_74625_half_map_1.map
AnnotationCryo-EM half map of KCa3.1_I/calmodulin channel in complex with SKA111.
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 I/calmodulin channel in complex...

Fileemd_74625_half_map_2.map
AnnotationCryo-EM half map of KCa3.1_I/calmodulin channel in complex with SKA111.
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 KCa3.1_I/calmodulin channel in complex with SKA111.

EntireName: Human KCa3.1_I/calmodulin channel in complex with SKA111.
Components
  • Complex: Human KCa3.1_I/calmodulin channel in complex with SKA111.
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: 5-methylnaphtho[1,2-d][1,3]thiazol-2-amine
  • Ligand: POTASSIUM ION
  • Ligand: CALCIUM ION

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Supramolecule #1: Human KCa3.1_I/calmodulin channel in complex with SKA111.

SupramoleculeName: Human KCa3.1_I/calmodulin channel in complex with SKA111.
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
Details: Residues 124-141 was not modeled due to lack of interpretable cryo-EM density and conformational flexibility.
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.75357 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LGALRRRKRL LEQEKSLAGW ALVLAGTGIG LMVLHAEMLW FGGCSWALYL FLVKCTISIS TFLLLCLIVA FHAKEVQLFM TDNGLRDWR VALTGRQAAQ IVLELVVCGL HPAPVRPGFL GQGEALLSLA MLLRLYLVPR AVLLRSGVLL NASYRSIGAL N QVRFRHWF ...String:
LGALRRRKRL LEQEKSLAGW ALVLAGTGIG LMVLHAEMLW FGGCSWALYL FLVKCTISIS TFLLLCLIVA FHAKEVQLFM TDNGLRDWR VALTGRQAAQ IVLELVVCGL HPAPVRPGFL GQGEALLSLA MLLRLYLVPR AVLLRSGVLL NASYRSIGAL N QVRFRHWF VAKLYMNTHP GRLLLGLTLG LWLTTAWVLS VAERQAVNAT GHLSDTLWLI PITFLTIGYG DVVPGTMWGK IV CLCTGVM GVCCTALLVA VVARKLEFNK AEKHVHNFMM DIQYTKEMKE SAARVLQEAW MFYKHTRRKE SHAARRHQRK LLA AINAFR QVRLKHRKLR EQVNSMVDIS KMHMILYDLQ QNLS

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: Homo sapiens (human)
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: 5-methylnaphtho[1,2-d][1,3]thiazol-2-amine

MacromoleculeName: 5-methylnaphtho[1,2-d][1,3]thiazol-2-amine / type: ligand / ID: 3 / Number of copies: 4 / Formula: A1C3U
Molecular weightTheoretical: 214.286 Da

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Macromolecule #4: POTASSIUM ION

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

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 16 / 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: 2.0 µm / Nominal defocus min: 1.0 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: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 205224
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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