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- PDB-1oiu: Structure of human Thr160-phospho CDK2/cyclin A complexed with a ... -

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Basic information

Entry
Database: PDB / ID: 1oiu
TitleStructure of human Thr160-phospho CDK2/cyclin A complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
KeywordsKINASE / TRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / ATP-BINDING / CELL CYCLE / CELL DIVISION / MITOSIS / PHOSPHORYLATION
Function / homology
Function and homology information


Activation of ATR in response to replication stress / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / G0 and Early G1 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of APC/C activators between G1/S and early anaphase / Senescence-Associated Secretory Phenotype (SASP) / PTK6 Regulates Cell Cycle / p53-Dependent G1 DNA Damage Response ...Activation of ATR in response to replication stress / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / G0 and Early G1 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of APC/C activators between G1/S and early anaphase / Senescence-Associated Secretory Phenotype (SASP) / PTK6 Regulates Cell Cycle / p53-Dependent G1 DNA Damage Response / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / CDK-mediated phosphorylation and removal of Cdc6 / Activation of the pre-replicative complex / Orc1 removal from chromatin / G2 Phase / Cyclin A:Cdk2-associated events at S phase entry / Meiotic recombination / Cyclin E associated events during G1/S transition / Regulation of TP53 Degradation / Regulation of TP53 Activity through Phosphorylation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Processing of DNA double-strand break ends / Factors involved in megakaryocyte development and platelet production / Ub-specific processing proteases / DNA Damage/Telomere Stress Induced Senescence / Cyclin A/B1/B2 associated events during G2/M transition / cellular response to luteinizing hormone stimulus / cellular response to cocaine / cell cycle G1/S phase transition / mitotic cell cycle phase transition / male pronucleus / female pronucleus / cellular response to insulin-like growth factor stimulus / cellular response to leptin stimulus / response to glucagon / cochlea development / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to platelet-derived growth factor stimulus / regulation of DNA replication / regulation of cyclin-dependent protein serine/threonine kinase activity / cyclin A1-CDK2 complex / cyclin E1-CDK2 complex / cyclin E2-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 / cellular response to estradiol stimulus / chromosome, telomeric region / animal organ regeneration / G1/S transition of mitotic cell cycle / positive regulation of fibroblast proliferation / 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 / cellular response to hypoxia / 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 / protein deubiquitination / centrosome / cell division / DNA repair / protein domain specific binding / viral process / protein serine/threonine kinase activity / protein phosphorylation / positive regulation of cell population proliferation / protein kinase binding / positive regulation of transcription, DNA-templated / magnesium ion binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Protein kinase domain / Cyclin, C-terminal domain / Cyclins signature. / Serine/Threonine protein kinases active-site signature. / Protein kinases ATP-binding region signature. / N-terminal region of cyclin_N / Cyclin, N-terminal domain / Protein kinase domain / Cyclin / Cyclin-like superfamily ...Protein kinase domain / Cyclin, C-terminal domain / Cyclins signature. / Serine/Threonine protein kinases active-site signature. / Protein kinases ATP-binding region signature. / N-terminal region of cyclin_N / Cyclin, N-terminal domain / Protein kinase domain / Cyclin / Cyclin-like superfamily / Cyclin-A, N-terminal / Protein kinase, ATP binding site / Cyclin-like / Protein kinase-like domain superfamily / Serine/threonine-protein kinase, active site / Cyclin, N-terminal / Cyclin, C-terminal domain / Protein kinase domain profile.
Cyclin-A2 / Cyclin-dependent kinase 2
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPratt, D.J. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2004
Title: N2-Substituted O6-Cyclohexylmethylguanine Derivatives: Potent Inhibitors of Cyclin-Dependent Kinases 1 and 2
Authors: Hardcastle, I.R. / Arris, C.E. / Bentley, J. / Boyle, F.T. / Chen, Y. / Curtin, N.J. / Endicott, J.A. / Gibson, A.E. / Golding, B.T. / Griffin, R.J. / Jewsbury, P. / Menyerol, J. / Mesguiche, V. / Newell, D.R. / Noble, M.E.M. / Pratt, D.J. / Wang, L.-Z. / Whitfield, H.J.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJun 26, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2004Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: 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
B: CYCLIN A2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,5249
Polymers128,4794
Non-polymers1,0465
Water11,638646
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7745
Polymers64,2392
Non-polymers5353
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7504
Polymers64,2392
Non-polymers5112
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
γ
α
β
Length a, b, c (Å)73.648, 133.778, 148.228
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper:

Code: given

IDMatrixVector
1(0.03157, -0.51405, 0.85718), (-0.50819, -0.74674, -0.4291), (0.86067, -0.42206, -0.28481)11.53561, 143.03769, 70.33099
2(0.04267, -0.49436, 0.86821), (-0.52579, -0.75004, -0.40124), (0.84955, -0.43937, -0.29193)9.42328, 142.78091, 71.95583

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Components

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Protein/peptide , 2 types, 4 molecules ACBD

#1: Protein/peptide CELL DIVISION PROTEIN KINASE 2 / / P33 PROTEIN KINASE / CDK2


Mass: 34354.770 Da / Num. of mol.: 2 / Details: PHOSPHORYLATED ON THR160
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein/peptide CYCLIN A2 / / CYCLIN A / CCNA2 / CCNA / CCN1


Mass: 29884.605 Da / Num. of mol.: 2 / Fragment: RESIDUES 174-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248

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Non-polymers , 4 types, 651 molecules

#3: Chemical ChemComp-N76 / 3-(6-CYCLOHEXYLMETHOXY-9H-PURIN-2-YLAMINO)-BENZENESULFONAMIDE


Mass: 402.471 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22N6O3S
#4: Chemical ChemComp-SGM / MONOTHIOGLYCEROL


Mass: 108.159 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2S / 3-Mercaptopropane-1,2-diol
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Magnesium
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 646 / Source method: isolated from a natural source / Formula: H2O / Water

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Details

Compound detailsCYCLIN CONTROLS THE CELL CYCLE AT THE G1/S (START) AND THE G2/M (MITOSIS) TRANSITIONS. KINASE ...CYCLIN CONTROLS THE CELL CYCLE AT THE G1/S (START) AND THE G2/M (MITOSIS) TRANSITIONS. KINASE INTERACTS WITH CYCLINS A, D, OR E. ACTIVITY OF CDK2 IS MAXIMAL DURING S PHASE AND G2. THE GLUTAMIC ACID RESIDUES INDICATED IN REMARK 470 BELOW HAVE MISSING ATOMS DUE TO RADIATION-INDUCED DECARBOXYLATION.

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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: 2.8 Å3/Da / Density % sol: 55.2 % / Description: USED DATA TO 3.5 A FOR MR
Crystal growpH: 7
Details: 0.7-0.85 M POTASSIUM CHLORIDE 1.1-1.25 M AMMONIUM SULFATE, 40 MM HEPES, PH 7.0 5 MM DITHIOTHREITOL, 10 MG/ML PROTEIN, 8M SODIUM FORMATE CRYO-PROTECTANT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.934
DetectorType: ADSC CCD / Detector: CCD / Date: May 10, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2→74.54 Å / Num. obs: 98449 / % possible obs: 99.1 % / Observed criterion σ(I): 1 / Redundancy: 3.22 % / Biso Wilson estimate: 26.72894 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 7.0519
Reflection shellResolution: 2→2.11 Å / Redundancy: 2.35 % / Rmerge(I) obs: 0.24 / Mean I/σ(I) obs: 3.11 / % possible all: 97.8

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Processing

Software
NameClassification
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1S
Resolution: 2→100 Å / SU B: 3.638 / SU ML: 0.105 / Cross valid method: THROUGHOUT / ESU R: 0.181 / ESU R Free: 0.164
RfactorNum. reflection% reflectionSelection details
Rfree0.2532 4923 5.03 %RANDOM
Rwork0.2158 ---
Obs-93478 99.14 %-
Displacement parametersBiso mean: 27.837 Å2
Baniso -1Baniso -2Baniso -3
1--0.51 Å20 Å20 Å2
2--0.34 Å20 Å2
3---0.17 Å2
Refinement stepCycle: LAST / Resolution: 2→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8649 0 69 646 9364

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