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- PDB-5v03: A positive allosteric modulator binding pocket in SK2 ion channel... -

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Basic information

Entry
Database: PDB / ID: 5v03
TitleA positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA
Components
  • Calmodulin
  • 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


Acetylcholine inhibits contraction of outer hair cells / 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 / : / : / : / : / : ...Acetylcholine inhibits contraction of outer hair cells / 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 protein autophosphorylation / negative regulation of peptidyl-threonine phosphorylation / inward rectifier potassium channel activity / : / type 3 metabotropic glutamate receptor binding / regulation of potassium ion transmembrane transport / positive regulation of peptidyl-threonine phosphorylation / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / positive regulation of DNA binding / Calmodulin induced events / 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 / response to corticosterone / 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 / regulation of synaptic vesicle exocytosis / nitric-oxide synthase binding / 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 / alpha-actinin binding / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / adenylate cyclase binding / regulation of ryanodine-sensitive calcium-release channel activity / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / positive regulation of protein serine/threonine kinase activity / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / regulation of synaptic vesicle endocytosis / 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 / enzyme regulator activity / activation of adenylate cyclase activity / phosphatidylinositol 3-kinase binding / positive regulation of nitric-oxide synthase activity / calcium channel inhibitor activity / Activation of AMPK downstream of NMDARs / presynaptic cytosol / cellular response to interferon-beta / Protein methylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / Ion homeostasis / eNOS activation / 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 / nitric-oxide synthase regulator activity / adenylate cyclase activator activity / sarcomere / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / response to amphetamine / regulation of cytokinesis
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 ...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 / : / Recoverin; domain 1 / 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
Chem-658 / Calmodulin-1 / Calmodulin-3 / Small conductance calcium-activated potassium channel protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)29,5726
Polymers29,0962
Non-polymers4764
Water3,171176
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2890 Å2
ΔGint-53 kcal/mol
Surface area15070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.092, 66.882, 65.381
Angle α, β, γ (deg.)90.00, 93.95, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-624-

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 / CaM


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, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
References: UniProt: P62158, UniProt: P0DP23*PLUS

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Non-polymers , 4 types, 180 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-658 / N-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine


Mass: 299.758 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14ClN5
#5: Chemical ChemComp-CA / CALCIUM ION


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


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.89 Å3/Da / Density % sol: 57.43 %
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: 1.58→50.47 Å / Num. obs: 41783 / % possible obs: 91.3 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Biso Wilson estimate: 29.58 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.032 / Net I/σ(I): 18.1
Reflection shellResolution: 1.58→1.66 Å / Redundancy: 2 % / Rmerge(I) obs: 0.268 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 8155 / CC1/2: 0.937 / % possible all: 60.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GOW

4gow


Resolution: 1.58→23.08 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.081 / SU Rfree Blow DPI: 0.081 / SU Rfree Cruickshank DPI: 0.08
RfactorNum. reflection% reflectionSelection details
Rfree0.22 2144 5.13 %RANDOM
Rwork0.194 ---
obs0.196 41767 91.2 %-
Displacement parametersBiso mean: 39.08 Å2
Baniso -1Baniso -2Baniso -3
1-3.6697 Å20 Å24.7558 Å2
2---4.0218 Å20 Å2
3---0.3521 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: 1 / Resolution: 1.58→23.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1849 0 28 177 2054
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011938HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.962611HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d742SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes370HARMONIC5
X-RAY DIFFRACTIONt_it1938HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion15.26
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion253SEMIHARMONIC5
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_contact2487SEMIHARMONIC4
LS refinement shellResolution: 1.58→1.62 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2478 -4.39 %
Rwork0.2381 1786 -
all0.2385 1868 -
obs--54.9 %
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)
11.83640.0702-0.34850.46340.05480.7441-0.06610.086-0.0055-0.0390.0227-0.0739-0.1468-0.00350.0433-0.0657-0.0064-0.0359-0.0879-0.0035-0.046146.307358.356932.1183
22.7075-2.62890.52462.9227-0.75850.558-0.2925-0.32940.07550.31670.2863-0.0442-0.0578-0.04320.0061-0.08240.0367-0.0147-0.0633-0.0192-0.112722.177357.704443.9098
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ B|* }
2X-RAY DIFFRACTION2{ R|* }

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