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- PDB-9o51: Cryo-EM structure of the human SK2-4 chimera/calmodulin channel c... -

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Basic information

Entry
Database: PDB / ID: 9o51
TitleCryo-EM structure of the human SK2-4 chimera/calmodulin channel complex in the Ca2+ free state
Components
  • Calmodulin-1
  • Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera
KeywordsTRANSPORT PROTEIN / Ion channel / Calcium / Potassium / Calmodulin
Function / homology
Function and homology information


Acetylcholine inhibits contraction of outer hair cells / intermediate conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / saliva secretion / small conductance calcium-activated potassium channel activity / membrane repolarization during atrial cardiac muscle cell action potential / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane ...Acetylcholine inhibits contraction of outer hair cells / intermediate conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / saliva secretion / small conductance calcium-activated potassium channel activity / membrane repolarization during atrial cardiac muscle cell action potential / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / inward rectifier potassium channel activity / positive regulation of potassium ion transmembrane transport / regulation of potassium ion transmembrane transport / cell volume homeostasis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / phospholipid translocation / 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 / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / alpha-actinin binding / positive regulation of T cell receptor signaling pathway / RHO GTPases activate PAKs / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / 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 / detection of calcium ion / potassium channel activity / 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 / cellular response to interferon-beta / Activation of AMPK downstream of NMDARs / presynaptic cytosol / Protein methylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / Ion homeostasis / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / regulation of calcium-mediated signaling / sperm midpiece / 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 / sarcomere / VEGFR2 mediated cell proliferation / protein serine/threonine kinase activator activity / VEGFR2 mediated vascular permeability / regulation of cytokinesis / positive regulation of protein secretion / spindle microtubule / positive regulation of receptor signaling pathway via JAK-STAT / Translocation of SLC2A4 (GLUT4) to the plasma membrane / calcium channel regulator activity / establishment of localization in cell / RAF activation / defense response / Transcriptional activation of mitochondrial biogenesis / response to calcium ion
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 / Small conductance calcium-activated potassium channel protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsCassell, S.J. / Khoshouei, M. / Wilhelm, W.A. / Whicher, J.R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Elife / Year: 2025
Title: Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules.
Authors: Samantha J Cassell / Weiyan Li / Simon Krautwald / Maryam Khoshouei / Yan Tony Lee / Joyce Hou / Wendy Guan / Stefan Peukert / Wilhelm Weihofen / Jonathan R Whicher /
Abstract: Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in ...Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2-4 chimeric channel in Ca-bound and Ca-free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3-S4 linker forms a hydrophobic constriction at the extracellular opening of the pore. Apamin binds to this extracellular constriction and blocks the exit of potassium ions. Furthermore, we identified a structurally related SK2 inhibitor and activator that bind to the transmembrane domains. The compounds exert opposing effects on gating by differentially modulating the conformation of the S6 helices. These results provide important mechanistic insights to facilitate the development of targeted SK2 channel therapeutics.
History
DepositionApr 9, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 9, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera
B: Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera
C: Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera
D: Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera
E: Calmodulin-1
F: Calmodulin-1
G: Calmodulin-1
H: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,17714
Polymers264,9398
Non-polymers2396
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Intermediate conductance calcium-activated potassium channel protein 4,Small conductance calcium-activated potassium channel protein 2 chimera / SKCa 4 / SKCa4 / hSK4 / Gardos channel / IKCa1 / hIK1 / KCa3.1 / Putative Gardos channel / hKCa4 / ...SKCa 4 / SKCa4 / hSK4 / Gardos channel / IKCa1 / hIK1 / KCa3.1 / Putative Gardos channel / hKCa4 / SK2 / SKCa 2 / SKCa2 / KCa2.2


Mass: 49382.164 Da / Num. of mol.: 4
Fragment: SK4 residues 1-15 + SK2 residues 124-412 + SK4 residues 306-428
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNN4, IK1, IKCA1, KCA4, SK4, KCNN2 / Production host: Homo sapiens (human) / References: UniProt: O15554, UniProt: Q9H2S1
#2: Protein
Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of human SK2-4 chimera/calmodulin channel complex in the Ca2+-free stateCOMPLEX#1-#20RECOMBINANT
2Human SK2-4 chimeric channelCOMPLEX#11RECOMBINANT
3Human calmodulinCOMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
22Homo sapiens (human)9606Expi293F
32Homo sapiens (human)9606Expi293F
43Homo sapiens (human)9606Expi293F
Buffer solutionpH: 8
Details: 20 mM Tris pH 8, 150 mM KCl, 5 mM EGTA, 0.005% GDN, 0.0005% CHS
SpecimenConc.: 8.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: UltrAuFoil R 1.2/0.4 200 mesh grids were glow-discharged for 30 seconds at 0.38 mBar with 15 mA using Glocube system
Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: UltrAuFoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K
Details: 5 uL of sample was applied to grids at 4 degree temperature with 100% humidity. After 30 seconds, grids were blotted for 5 seconds with blot force 25 and plunged into liquid ethane.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 0.01 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.25 sec. / Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8928
Details: Images were collected in EER format with 50 fractions
EM imaging opticsSpherical aberration corrector: Microscope has a Cs corrector

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
7PHENIX1.21.2_5419model fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 8200000
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 386845 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 9O48

9o48


Accession code: 9O48 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00112536
ELECTRON MICROSCOPYf_angle_d0.31417032
ELECTRON MICROSCOPYf_dihedral_angle_d3.031716
ELECTRON MICROSCOPYf_chiral_restr0.0332032
ELECTRON MICROSCOPYf_plane_restr0.0022108

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