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- PDB-1h08: CDK2 in complex with a disubstituted 2, 4-bis anilino pyrimidine ... -

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Basic information

Entry
Database: PDB / ID: 1h08
TitleCDK2 in complex with a disubstituted 2, 4-bis anilino pyrimidine CDK4 inhibitor
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / MITOSIS
Function / homology
Function and homology information


Orc1 removal from chromatin / G0 and Early G1 / Activation of ATR in response to replication stress / Regulation of APC/C activators between G1/S and early anaphase / SCF(Skp2)-mediated degradation of p27/p21 / Senescence-Associated Secretory Phenotype (SASP) / DNA Damage/Telomere Stress Induced Senescence / Processing of DNA double-strand break ends / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of TP53 Degradation ...Orc1 removal from chromatin / G0 and Early G1 / Activation of ATR in response to replication stress / Regulation of APC/C activators between G1/S and early anaphase / SCF(Skp2)-mediated degradation of p27/p21 / Senescence-Associated Secretory Phenotype (SASP) / DNA Damage/Telomere Stress Induced Senescence / Processing of DNA double-strand break ends / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of TP53 Degradation / G2 Phase / Regulation of TP53 Activity through Phosphorylation / Activation of the pre-replicative complex / Factors involved in megakaryocyte development and platelet production / Meiotic recombination / PTK6 Regulates Cell Cycle / CDK-mediated phosphorylation and removal of Cdc6 / Cyclin A:Cdk2-associated events at S phase entry / p53-Dependent G1 DNA Damage Response / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-dependent DNA replication initiation / Y chromosome / cyclin-dependent protein kinase activity / X chromosome / histone phosphorylation / centrosome duplication / centriole replication / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / Cajal body / cellular response to nitric oxide / mitotic G1 DNA damage checkpoint / cyclin binding / regulation of gene silencing / potassium ion transport / meiotic cell cycle / chromosome, telomeric region / G1/S transition of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / anaphase-promoting complex-dependent catabolic process / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Ras protein signal transduction / transcription factor complex / G2/M transition of mitotic cell cycle / regulation of signal transduction by p53 class mediator / DNA replication / endosome / peptidyl-serine phosphorylation / centrosome / cell division / DNA repair / protein domain specific binding / protein serine/threonine kinase activity / protein phosphorylation / positive regulation of cell population proliferation / positive regulation of transcription, DNA-templated / magnesium ion binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain profile. / Protein kinase-like domain superfamily / Protein kinase domain / Protein kinase, ATP binding site / Protein kinase domain / Protein kinases ATP-binding region signature.
Cyclin-dependent kinase 2
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBreault, G.A. / Ellston, R.P.A. / Green, S. / James, S.R. / Jewsbury, P.J. / Midgley, C.J. / Minshull, C.A. / Pauptit, R.A. / Tucker, J.A. / Pease, J.E.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2003
Title: Cyclin-Dependent Kinase 4 Inhibitors as a Treatment for Cancer. Part 1: Identification and Optimisation of Substituted 4,6-Bis Anilino Pyrimidines
Authors: Beattie, J.F. / Breault, G.A. / Ellston, R.P.A. / Green, S. / Jewsbury, P.J. / Midgley, C.J. / Naven, R.T. / Minshull, C.A. / Pauptit, R.A. / Tucker, J.A. / Pease, J.E.
#1: Journal: J.Med.Chem. / Year: 1996
Title: High-Resolution Crystal Structures of Human Cyclin-Dependent Kinase 2 with and without ATP: Bound Waters and Natural Ligand as a Guide for Inhibitor Design
Authors: Schulze-Gahmen, U. / De Bondt, H. / Kim, S.-H.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJun 11, 2002Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 11, 2003Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2011Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Other / Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CELL DIVISION PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0114
Polymers34,0031
Non-polymers1,0093
Water3,225179
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)53.218, 71.900, 72.013
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein/peptide CELL DIVISION PROTEIN KINASE 2 / / P33 PROTEIN KINASE


Mass: 34002.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 / References: UniProt: P24941, EC: 2.7.1.37
#2: Chemical ChemComp-BYP / (2R)-1-{4-[(4-ANILINO-5-BROMOPYRIMIDIN-2-YL)AMINO]PHENOXY}-3-(DIMETHYLAMINO)PROPAN-2-OL


Mass: 458.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24BrN5O2
#3: Chemical ChemComp-BWP / (2S)-1-{4-[(4-ANILINO-5-BROMOPYRIMIDIN-2-YL)AMINO]PHENOXY}-3-(DIMETHYLAMINO)PROPAN-2-OL


Mass: 458.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24BrN5O2
#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 / Glycerol
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / Source method: isolated from a natural source / Formula: H2O / Water

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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 Å3/Da / Density % sol: 38 %
Crystal growpH: 7
Details: PROTEIN AT 10MG/ML WELL BUFFER CONTAINING 17.5% PEG3350, 200MM HEPES, PH7.0, 100MM AMMONIUM ACETATE, pH 7.00
Crystal grow
*PLUS
Method: unknown / Details: Lawrie, A.M., (1997) Nat.Struct.Biol., 4, 796.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.93
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 15, 1998 / Details: SAGITALLY FOCUSSING GE (220)
RadiationMonochromator: DIAMOND (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.93 Å / Relative weight: 1
ReflectionResolution: 1.79→36.78 Å / Num. obs: 26414 / % possible obs: 99.5 % / Redundancy: 4.1 % / Biso Wilson estimate: 23.9 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 18.5
Reflection shellResolution: 1.79→1.89 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.455 / Mean I/σ(I) obs: 2.3 / % possible all: 99.7

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Processing

Software
NameVersionClassification
CNX2000.1refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→36.78 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1223590.24 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: RESIDUES 36 - 43 AND 154 - 160 ARE NOT VISIBLE IN THE ELECTRON DENSITY MAP
RfactorNum. reflection% reflectionSelection details
Rfree0.242 1303 5 %RANDOM
Rwork0.213 ---
Obs-26090 99.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.5559 Å2 / ksol: 0.358635 e/Å3
Displacement parametersBiso mean: 33.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å20 Å20 Å2
2---7.76 Å20 Å2
3---8.23 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.23 Å
Luzzati d res low-25 Å
Luzzati sigma a0.27 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 1.8→36.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2242 0 64 179 2485
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal target
c_bond_d0.006
c_bond_d_na
c_bond_d_prot
c_angle_d
c_angle_d_na
c_angle_d_prot
c_angle_deg1.2
c_angle_deg_na
c_angle_deg_prot
c_dihedral_angle_d22.4
c_dihedral_angle_d_na
c_dihedral_angle_d_prot
c_improper_angle_d0.74
c_improper_angle_d_na
c_improper_angle_d_prot
c_mcbond_it1.451.5
c_mcangle_it2.332
c_scbond_it2.122
c_scangle_it3.132.5
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.4 225 5.2 %
Rwork0.362 4065 -
Obs--99.5 %
Xplor file

Refinement-ID: X-RAY DIFFRACTION

Serial noParam fileTopol file
1PROTEIN_REP.PARAMPROTEIN.TOP
2WATER_REP.PARAMWATER.TOP
3ION.PARAMION.TOP

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