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- PDB-5v02: A positive allosteric modulator binding pocket in SK2 ion channel... -

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Basic information

Entry
Database: PDB / ID: 5v02
TitleA positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA
Components
  • Calmodulin-1
  • Small conductance calcium-activated potassium channel protein 2
KeywordsTRANSPORT PROTEIN/Metal Binding protein / calcium-activated ion channels / activator / calmodulin / TRANSPORT PROTEIN-Metal Binding protein complex
Function / homology
Function and homology information


small conductance calcium-activated potassium channel activity / Acetylcholine inhibits contraction of outer hair cells / Ca2+ activated K+ channels / membrane repolarization during atrial cardiac muscle cell action potential / calcium-activated potassium channel activity / inward rectifier potassium channel activity / regulation of potassium ion transmembrane transport / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers ...small conductance calcium-activated potassium channel activity / Acetylcholine inhibits contraction of outer hair cells / Ca2+ activated K+ channels / membrane repolarization during atrial cardiac muscle cell action potential / calcium-activated potassium channel activity / inward rectifier potassium channel activity / regulation of potassium ion transmembrane transport / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / Activation of RAC1 downstream of NMDARs / mitochondrion-endoplasmic reticulum membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / regulation of cardiac muscle cell action potential / autophagosome membrane docking / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / alpha-actinin binding / protein phosphatase activator activity / RHO GTPases activate PAKs / positive regulation of cyclic-nucleotide phosphodiesterase activity / positive regulation of phosphoprotein phosphatase activity / Ion transport by P-type ATPases / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction / calcium channel inhibitor activity / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / eNOS activation / Activation of AMPK downstream of NMDARs / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of protein dephosphorylation / potassium ion transmembrane transport / voltage-gated potassium channel complex / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / titin binding / positive regulation of protein autophosphorylation / sperm midpiece / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / regulation of cytokinesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / spindle microtubule / potassium ion transport / Stimuli-sensing channels / Z disc / cellular response to type II interferon / spindle pole / response to calcium ion / RAS processing / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Inactivation, recovery and regulation of the phototransduction cascade
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 / Helix Hairpins - #70 / 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 / Helix Hairpins - #70 / 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 / Helix Hairpins / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
6-(trifluoromethoxy)-1,3-benzothiazol-2-amine / Calmodulin-1 / Small conductance calcium-activated potassium channel protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsLiu, S.
CitationJournal: Structure / Year: 2018
Title: An Intracellular Allosteric Modulator Binding Pocket in SK2 Ion Channels Is Shared by Multiple Chemotypes.
Authors: Cho, L.T. / Alexandrou, A.J. / Torella, R. / Knafels, J. / Hobbs, J. / Taylor, T. / Loucif, A. / Konopacka, A. / Bell, S. / Stevens, E.B. / Pandit, J. / Horst, R. / Withka, J.M. / Pryde, D.C. ...Authors: Cho, L.T. / Alexandrou, A.J. / Torella, R. / Knafels, J. / Hobbs, J. / Taylor, T. / Loucif, A. / Konopacka, A. / Bell, S. / Stevens, E.B. / Pandit, J. / Horst, R. / Withka, J.M. / Pryde, D.C. / Liu, S. / Young, G.T.
History
DepositionFeb 28, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 7, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Small conductance calcium-activated potassium channel protein 2
R: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,6958
Polymers29,0962
Non-polymers5996
Water1,13563
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, crystalllography 2-fold symmetry generate biological dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3160 Å2
ΔGint-49 kcal/mol
Surface area15450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.762, 66.554, 65.131
Angle α, β, γ (deg.)90.00, 94.27, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-619-

HOH

21B-625-

HOH

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Components

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Protein , 2 types, 2 molecules BR

#1: Protein Small conductance calcium-activated potassium channel protein 2 / SKCa2 / KCa2.2


Mass: 12243.395 Da / Num. of mol.: 1 / Fragment: UNP residues 395-486
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNN2
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
References: UniProt: Q9H2S1
#2: Protein Calmodulin-1 /


Mass: 16852.545 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
References: UniProt: P0DP23

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Non-polymers , 5 types, 69 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-657 / 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine / Riluzole / Riluzole


Mass: 234.198 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H5F3N2OS / Comment: medication*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.87 Å3/Da / Density % sol: 57.1 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: ammonia sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.78→50.504 Å / Num. obs: 31198 / % possible obs: 98.5 % / Observed criterion σ(I): 0 / Redundancy: 3.3 % / Biso Wilson estimate: 35.36 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.039 / Net I/σ(I): 16
Reflection shellResolution: 1.78→1.789 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.529 / Mean I/σ(I) obs: 2 / Num. unique obs: 304 / CC1/2: 0.783 / % possible all: 98.7

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GOW

4gow


Resolution: 1.78→23.02 Å / Cor.coef. Fo:Fc: 0.9472 / Cor.coef. Fo:Fc free: 0.9444 / SU R Cruickshank DPI: 0.101 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.099 / SU Rfree Blow DPI: 0.095 / SU Rfree Cruickshank DPI: 0.097
RfactorNum. reflection% reflectionSelection details
Rfree0.2148 1536 4.93 %RANDOM
Rwork0.1938 ---
obs0.1949 31179 97.97 %-
Displacement parametersBiso mean: 45.5 Å2
Baniso -1Baniso -2Baniso -3
1-4.4931 Å20 Å23.7266 Å2
2---6.5645 Å20 Å2
3---2.0715 Å2
Refine analyzeLuzzati coordinate error obs: 0.238 Å
Refinement stepCycle: 1 / Resolution: 1.78→23.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1889 0 33 63 1985
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011943HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.992610HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d739SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes287HARMONIC5
X-RAY DIFFRACTIONt_it1943HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.71
X-RAY DIFFRACTIONt_other_torsion16.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion255SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2291SEMIHARMONIC4
LS refinement shellResolution: 1.78→1.84 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2914 135 4.96 %
Rwork0.233 2585 -
all0.236 2720 -
obs--93.29 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.07960.0249-1.04120.38440.17861.2823-0.05980.15640.0352-0.03090.0411-0.0851-0.1256-0.04850.0187-0.2068-0.0058-0.038-0.22620.0014-0.199146.294258.325431.868
22.9387-2.54110.63742.9256-0.87290.6686-0.2837-0.36150.08880.31820.2726-0.0245-0.0948-0.05850.0111-0.18380.0311-0.0108-0.1513-0.0155-0.214221.931757.692143.4942
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ B|* }
2X-RAY DIFFRACTION2{ R|* }

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