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- PDB-1pxo: HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR [4-(... -

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Basic information

Entry
Database: PDB / ID: 1pxo
TitleHUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR [4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine
ComponentsCell division protein kinase 2
KeywordsTRANSFERASE / PROTEIN KINASE / CELL CYCLE / PHOSPHORYLATION / CELL DIVISION / MITOSIS / INHIBITION / SERINE/THREONINE-PROTEIN KINASE / ATP-BINDING / 3D-STRUCTURE.
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: 1.96 Å
AuthorsWang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Mezna, M. / Jackson, W. / Midgley, C. / Griffiths, G. / McNae, I. / Wu, S.Y. / McInnes, C. / Zheleva, D. / Walkinshaw, M.D. / Fischer, P.M.
Citation
Journal: J.Med.Chem. / Year: 2004
Title: 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
Authors: Wang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Mezna, M. / Jackson, W. / Midgley, C. / Griffiths, G. / Fleming, I. / Green, S. / McNae, I. / Wu, S.Y. / McInnes, C. / Zheleva, D. / Walkinshaw, M.D. / Fischer, P.M.
#1: Journal: Structure / Year: 2003
Title: Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.
Authors: Wu, S.Y. / McNae, I. / Kontopidis, G. / McClue, S.J. / McInnes, C. / Stewart, K.J. / Wang, S. / Zheleva, D.I. / Marriage, H. / Lane, D.P. / Taylor, P. / Fischer, P.M. / Walkinshaw, M.D.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jul 4, 2003 / Release: Apr 13, 2004
RevisionDateData content typeGroupProviderType
1.0Apr 13, 2004Structure modelrepositoryInitial release
1.1Apr 29, 2008Structure modelVersion format compliance
1.2Jul 13, 2011Structure modelVersion format compliance
Remark 600HETEROGEN partial CK7 500 has alternate conformation with HOH 501,502,503,504,505,506,507,508,and 509.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cell division protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3052
Polymers33,9761
Non-polymers3281
Water3,027168
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)53.489, 71.987, 72.362
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: 33976.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2 / Cell line (production host): Hi5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P24941, Transferases, Transferring phosphorus-containing groups, Phosphotransferases with an alcohol group as acceptor
#2: Chemical ChemComp-CK7 / [4-(2-AMINO-4-METHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-(3-NITRO-PHENYL)-AMINE


Mass: 328.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 2.05 Å3/Da / Density % sol: 39.97 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: PEG 6000, NA-HEPES, pH 7.8, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.1 / Wavelength: 1.488 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.488 Å / Relative weight: 1
ReflectionResolution: 1.96→15 Å / Num. obs: 20604 / % possible obs: 99.4 % / Redundancy: 10.97 % / Biso Wilson estimate: 13.6 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 22.4
Reflection shellResolution: 1.96→2.07 Å / Rmerge(I) obs: 0.165 / Mean I/σ(I) obs: 7.7 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CNS1refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1HCL
Resolution: 1.96→14.99 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1664384.74 / Data cutoff high rms absF: 1664384.74 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.235 1045 5.1 %RANDOM
Rwork0.217 ---
All0.22 ---
Obs0.217 20574 98.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 74.2328 Å2 / ksol: 0.399945 e/Å3
Displacement parametersBiso mean: 32.1 Å2
Baniso -1Baniso -2Baniso -3
1--1.54 Å20 Å20 Å2
2---5.8 Å20 Å2
3---7.34 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 1.96→14.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2375 0 32 168 2575
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_deg1.3
c_angle_deg_na
c_angle_deg_prot
c_dihedral_angle_d22
c_dihedral_angle_d_na
c_dihedral_angle_d_prot
c_improper_angle_d1.16
c_improper_angle_d_na
c_improper_angle_d_prot
c_mcbond_it1.91.5
c_mcangle_it3.252
c_scbond_it2.362
c_scangle_it3.592.5
LS refinement shellResolution: 1.96→2.07 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.262 142 4.5 %
Rwork0.252 3044 -
Obs-3044 93.3 %
Xplor file

Refinement-ID: X-RAY DIFFRACTION

Serial noParam fileTopol file
1PROTEIN_REP.PARAMPROTEIN.TOP
2C3K_PAR.TXTC3K_TOP.TXT
3WATER_REP.PARAMWATER.TOP

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