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- EMDB-72519: Cryo EM structure of KCa3.1_R355K_I/calmodulin channel in complex... -

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Basic information

Entry
Database: EMDB / ID: EMD-72519
TitleCryo EM structure of KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
Map dataCryo EM map of KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
Sample
  • Complex: Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: Rimtuzalcap
  • 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 / Ca2+ activated K+ channels / small conductance calcium-activated potassium channel activity / 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 / cell volume homeostasis ...intermediate conductance calcium-activated potassium channel activity / saliva secretion / Ca2+ activated K+ channels / small conductance calcium-activated potassium channel activity / 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 / 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 / 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 / regulation of cell communication by electrical coupling involved in cardiac conduction / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / calcineurin-mediated signaling / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / positive regulation of T cell receptor signaling pathway / regulation of ryanodine-sensitive calcium-release channel activity / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / immune system process / potassium channel activity / detection of calcium ion / regulation of cardiac muscle contraction / catalytic complex / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel inhibitor activity / Activation of AMPK downstream of NMDARs / presynaptic cytosol / cellular response to interferon-beta / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Protein methylation / Ion homeostasis / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / FCERI mediated Ca+2 mobilization / calcium channel complex / substantia nigra development / regulation of heart rate / FCGR3A-mediated IL10 synthesis / Ras activation upon Ca2+ influx through NMDA receptor / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calyx of Held / adenylate cyclase activator activity / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / sarcomere / regulation of cytokinesis / positive regulation of protein secretion / VEGFR2 mediated vascular permeability / spindle microtubule / positive regulation of receptor signaling pathway via JAK-STAT / Translocation of SLC2A4 (GLUT4) to the plasma membrane / establishment of localization in cell / calcium channel regulator activity / potassium ion transport / RAF activation / defense response / Transcriptional activation of mitochondrial biogenesis / 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: 4.73 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: Nat Commun / Year: 2026
Title: Structural basis for the subtype-selectivity of K2.2 channel activators.
Authors: Young-Woo Nam / Alena Ramanishka / Yang Xu / Rose Marie Haynes Yasuda / Joshua A Nasburg / Dohyun Im / Meng Cui / K George Chandy / Heike Wulff / Miao Zhang /
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 NS309-bound K2.2 and K3.1, in addition to structures of rimtuzalcap-bound K2.2 and mutant K3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K2.2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in K2.2 requiring conformational changes. In K2.2, calmodulin's N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In K3.1, calmodulin's N-lobes are closer to each other and constrained by K3.1's HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in K3.1's HB helix with lysine (K3.1_R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting K2.2 channels.
History
DepositionSep 5, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateFeb 11, 2026-
Current statusFeb 11, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72519.png

Downloads & links

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Map

FileDownload / File: emd_72519.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo EM map of KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.68 Å/pix.
x 256 pix.
= 430.08 Å		1.68 Å/pix.
x 256 pix.
= 430.08 Å		1.68 Å/pix.
x 256 pix.
= 430.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.68 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 8.800000000000001
Minimum - Maximum-39.388190000000002 - 61.305619999999998
Average (Standard dev.)-0.000000000000237 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 430.08 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 R355K I/calmodulin channel in...

Fileemd_72519_half_map_1.map
AnnotationCryo EM half map of KCa3.1_R355K_I/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 KCa3.1 R355K I/calmodulin channel in...

Fileemd_72519_half_map_2.map
AnnotationCryo EM half map of KCa3.1_R355K_I/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 : Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap

EntireName: Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
Components
  • Complex: Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
    • Protein or peptide: Intermediate conductance calcium-activated potassium channel protein 4
    • Protein or peptide: Calmodulin-1
  • Ligand: POTASSIUM ION
  • Ligand: Rimtuzalcap
  • Ligand: CALCIUM ION

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Supramolecule #1: Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap

SupramoleculeName: Human KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap
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: 42.570617 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 KLKHRKLREQ 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: 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: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #4: Rimtuzalcap

MacromoleculeName: Rimtuzalcap / type: ligand / ID: 4 / Number of copies: 4 / Formula: A1B92
Molecular weightTheoretical: 378.42 Da

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 4 / 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: 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:

9oa8

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.73 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 77867
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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