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- PDB-5n9k: Crystal structure of human Protein kinase CK2 catalytic subunit i... -

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Basic information

Entry
Database: PDB / ID: 5n9k
TitleCrystal structure of human Protein kinase CK2 catalytic subunit in complex with the ATP-competitive, tight-binding dibenzofuran inhibitor TF107 (5)
ComponentsCasein kinase II subunit alpha
KeywordsTRANSFERASE / Protein kinase / CK2 / Casein kinase 2 / Protein phosphorylation / ATP-competitive inhititors / dibenzofuran derivatives / TIGHT-BINDING INHIBITORS
Function / homology
Function and homology information


Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK / positive regulation of aggrephagy / regulation of chromosome separation / protein kinase CK2 complex / WNT mediated activation of DVL / Condensation of Prometaphase Chromosomes / symbiont-mediated disruption of host cell PML body / Phosphorylation and nuclear translocation of the CRY:PER:kinase complex / Regulation of CDH1 posttranslational processing and trafficking to plasma membrane / Receptor Mediated Mitophagy ...Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK / positive regulation of aggrephagy / regulation of chromosome separation / protein kinase CK2 complex / WNT mediated activation of DVL / Condensation of Prometaphase Chromosomes / symbiont-mediated disruption of host cell PML body / Phosphorylation and nuclear translocation of the CRY:PER:kinase complex / Regulation of CDH1 posttranslational processing and trafficking to plasma membrane / Receptor Mediated Mitophagy / Sin3-type complex / Synthesis of PC / negative regulation of apoptotic signaling pathway / negative regulation of signal transduction by p53 class mediator / Maturation of hRSV A proteins / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / negative regulation of double-strand break repair via homologous recombination / positive regulation of Wnt signaling pathway / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / Signal transduction by L1 / Wnt signaling pathway / Hsp90 protein binding / peptidyl-serine phosphorylation / PML body / SPOP-mediated proteasomal degradation of PD-L1(CD274) / Regulation of PTEN stability and activity / kinase activity / positive regulation of protein catabolic process / double-strand break repair / rhythmic process / KEAP1-NFE2L2 pathway / positive regulation of cell growth / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / protein folding / heterochromatin formation / Regulation of TP53 Activity through Phosphorylation / regulation of cell cycle / non-specific serine/threonine protein kinase / negative regulation of translation / protein stabilization / protein serine kinase activity / apoptotic process / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA damage response / positive regulation of DNA-templated transcription / chromatin / signal transduction / DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Casein Kinase 2, subunit alpha / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Casein Kinase 2, subunit alpha / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-8QK / ACETATE ION / Casein kinase II subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.643 Å
AuthorsSchnitzler, A. / Gratz, A. / Bollacke, A. / Weyrich, M. / Kucklaender, U. / Wuensch, B. / Goetz, C. / Niefind, K. / Jose, J.
Citation
Journal: Pharmaceuticals / Year: 2018
Title: A pi-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors.
Authors: Schnitzler, A. / Gratz, A. / Bollacke, A. / Weyrich, M. / Kucklander, U. / Wunsch, B. / Gotz, C. / Niefind, K. / Jose, J.
#1: Journal: J. Mol. Biol. / Year: 2003
Title: Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit.
Authors: Ermakova, I. / Boldyreff, B. / Issinger, O.G. / Niefind, K.
#2: Journal: J. Mol. Biol. / Year: 2005
Title: Inclining the purine base binding plane in protein kinase CK2 by exchanging the flanking side-chains generates a preference for ATP as a cosubstrate.
Authors: Yde, C.W. / Ermakova, I. / Issinger, O.G. / Niefind, K.
#3: Journal: Pharmaceuticals (Basel) / Year: 2017
Title: Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3-d]pyrimidine-Based Inhibitor.
Authors: Niefind, K. / Bischoff, N. / Golub, A.G. / Bdzhola, V.G. / Balanda, A.O. / Prykhod'ko, A.O. / Yarmoluk, S.M.
#4: Journal: Biochim. Biophys. Acta / Year: 2012
Title: TF--a novel cell-permeable and selective inhibitor of human protein kinase CK2 induces apoptosis in the prostate cancer cell line LNCaP.
Authors: Goetz, C. / Gratz, A. / Kucklaender, U. / Jose, J.
History
DepositionFeb 25, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 18, 2018Group: Data collection / Database references / Category: citation / Item: _citation.country / _citation.journal_id_ISSN
Revision 1.3Apr 25, 2018Group: Data collection / Database references / Category: citation / Item: _citation.journal_abbrev
Revision 1.4Jan 17, 2024Group: 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
A: Casein kinase II subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,9159
Polymers40,0671
Non-polymers8498
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1450 Å2
ΔGint-2 kcal/mol
Surface area15500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.876, 45.670, 63.753
Angle α, β, γ (deg.)90.00, 111.14, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Casein kinase II subunit alpha / CK II alpha


Mass: 40066.742 Da / Num. of mol.: 1 / Mutation: Deletion of C-terminal residues 336-391
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSNK2A1, CK2A1 / Production host: Escherichia coli (E. coli)
References: UniProt: P68400, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-8QK / 1,3-bis(chloranyl)-6-[(~{E})-(4-methoxyphenyl)iminomethyl]dibenzofuran-2,7-diol


Mass: 402.228 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H13Cl2NO4
#3: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 1.96 Å3/Da / Density % sol: 37.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: Prior to the crystallization the inhibitor was solubilized in 100 % DMSO in a concentration of 10 mM. Then, this inhibitor stock solution was mixed in a Ratio of 1:10 with human CK2alpha ...Details: Prior to the crystallization the inhibitor was solubilized in 100 % DMSO in a concentration of 10 mM. Then, this inhibitor stock solution was mixed in a Ratio of 1:10 with human CK2alpha (construct 1-335; solved with a Protein concentration of 8-10 mg/ml in 500 mM sodium chloride, 25 mM Tris/HCl pH 8.5). After a short time of incubation this mixture were mixed with reservoir solution [32 % (w/v) PEG4000, 0.2 M ammonium acetate, 0.1 M citrate pH 5.6] in a ratio of 2.5:1. 3.5 microliter of this final mixture was then equilibrated against the reservoir solution. The crystal growth was induced by seeding with 150 nanoliter seed suspension after an equilibration time of two days.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.64→45.67 Å / Num. obs: 37660 / % possible obs: 99 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.036 / Rsym value: 0.036 / Net I/σ(I): 17
Reflection shellResolution: 1.64→1.67 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.645 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1606 / CC1/2: 0.716 / Rsym value: 0.645 / % possible all: 87

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PVR

2pvr


Resolution: 1.643→36.22 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.76
RfactorNum. reflection% reflection
Rfree0.1843 1826 4.85 %
Rwork0.1638 --
obs0.1648 37635 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.643→36.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2779 0 57 249 3085
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042977
X-RAY DIFFRACTIONf_angle_d0.684030
X-RAY DIFFRACTIONf_dihedral_angle_d12.8341764
X-RAY DIFFRACTIONf_chiral_restr0.049409
X-RAY DIFFRACTIONf_plane_restr0.004523
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6432-1.68770.29941390.28592504X-RAY DIFFRACTION91
1.6877-1.73730.2731420.25392734X-RAY DIFFRACTION100
1.7373-1.79340.23991330.23362759X-RAY DIFFRACTION100
1.7934-1.85750.22791610.20182776X-RAY DIFFRACTION100
1.8575-1.93190.21531380.1882764X-RAY DIFFRACTION99
1.9319-2.01980.21181620.17922711X-RAY DIFFRACTION100
2.0198-2.12620.18451320.17092781X-RAY DIFFRACTION99
2.1262-2.25940.18851400.16312753X-RAY DIFFRACTION100
2.2594-2.43390.19221390.16122784X-RAY DIFFRACTION100
2.4339-2.67870.1751340.1672784X-RAY DIFFRACTION100
2.6787-3.06620.19991430.16542794X-RAY DIFFRACTION99
3.0662-3.86230.15661340.14272801X-RAY DIFFRACTION99
3.8623-36.22870.15771290.14552864X-RAY DIFFRACTION99
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)
13.5709-0.6121-0.2091.55860.36473.2557-0.0152-0.3279-0.6838-0.11180.00070.21960.5867-0.33180.0450.3519-0.0503-0.0390.23530.08680.4004-3.5642-10.033448.2132
22.5019-2.01020.27485.11790.94291.99460.0875-0.0451-0.3050.1674-0.24130.34290.1366-0.5430.10270.2303-0.07540.00460.48290.07190.3538-25.715410.249544.7689
34.1093-1.57121.06971.8807-0.95641.05630.066-0.2369-0.4033-0.02590.04170.38630.0451-0.2902-0.10990.1639-0.0470.01530.38860.08090.314-22.54596.825347.0264
43.2311.53020.62251.41880.82040.9597-0.1831-0.18160.4115-0.11620.17690.273-0.1909-0.1451-0.01460.23850.01490.01610.29420.04110.2416-5.595216.724651.2002
52.02520.0984-0.13021.27730.22361.94350.0318-0.007-0.017-0.15330.00580.0621-0.03940.0172-0.04370.1731-0.0011-0.01940.13190.03020.15721.98377.552637.75
61.3013-0.08920.42373.76810.77812.13010.0101-0.1480.06280.00410.0343-0.14-0.10290.1889-0.04120.1258-0.00640.01360.21110.00260.179710.282513.458549.4208
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 24 )
2X-RAY DIFFRACTION2chain 'A' and (resid 25 through 58 )
3X-RAY DIFFRACTION3chain 'A' and (resid 59 through 108 )
4X-RAY DIFFRACTION4chain 'A' and (resid 109 through 149 )
5X-RAY DIFFRACTION5chain 'A' and (resid 150 through 280 )
6X-RAY DIFFRACTION6chain 'A' and (resid 281 through 330 )

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