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- PDB-1y91: Crystal structure of human CDK2 complexed with a pyrazolo[1,5-a]p... -

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Entry
Database: PDB / ID: 1y91
TitleCrystal structure of human CDK2 complexed with a pyrazolo[1,5-a]pyrimidine inhibitor
ComponentsCell division protein kinase 2
KeywordsTRANSFERASE / Serine/Threonine protein kinase / CDK2 / ATP-binding / Cell cycle / mitosis / phosphorylation / pyrazolopyrimidine inhibitor
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 / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsWilliamson, D.S. / Parratt, M.J. / Torrance, C.J. / Bower, J.F. / Moore, J.D. / Richardson, C.M. / Dokurno, P. / Cansfield, A.D. / Francis, G.L. / Hebdon, R.J. / Howes, R. / Jackson, P.S. / Lockie, A.M. / Murray, J.B. / Nunns, C.L. / Powles, J. / Robertson, A. / Surgenor, A.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2.
Authors: Williamson, D.S. / Parratt, M.J. / Bower, J.F. / Moore, J.D. / Richardson, C.M. / Dokurno, P. / Cansfield, A.D. / Francis, G.L. / Hebdon, R.J. / Howes, R. / Jackson, P.S. / Lockie, A.M. / Murray, J.B. / Nunns, C.L. / Powles, J. / Robertson, A. / Surgenor, A.E. / Torrance, C.J.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Dec 14, 2004 / Release: Feb 8, 2005
RevisionDateData content typeGroupProviderType
1.0Feb 8, 2005Structure modelrepositoryInitial release
1.1Apr 30, 2008Structure modelVersion format compliance
1.2Jul 13, 2011Structure modelVersion format compliance

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Structure visualization

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Assembly

Deposited unit
A: Cell division protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4482
Polymers33,9761
Non-polymers4721
Water3,423190
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)53.372, 71.423, 72.004
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 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF21 / References: UniProt: P24941, EC: 2.7.1.37
#2: Chemical ChemComp-CT9 / 4-[5-(TRANS-4-AMINOCYCLOHEXYLAMINO)-3-ISOPROPYLPYRAZOLO[1,5-A]PYRIMIDIN-7-YLAMINO]-N,N-DIMETHYLBENZENESULFONAMIDE


Mass: 471.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H33N7O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 37.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: Peg 3350, Hepes, Ammonium acetate, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 9, 2003 / Details: mirrors
RadiationMonochromator: MSC/Osmic Blue / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30 Å / Num. all: 24371 / Num. obs: 24371 / % possible obs: 92.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.65 % / Biso Wilson estimate: 18.4 Å2 / Rmerge(I) obs: 0.085 / Net I/σ(I): 7.8
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 1.92 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.2 / Num. unique all: 2575 / % possible all: 64.2

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Processing

Software
NameVersionClassification
REFMAC5.1.19refinement
CrystalClear(MSC/RIGAKU)data reduction
d*TREKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1B39
Resolution: 2.15→25 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.886 / SU B: 8.389 / SU ML: 0.214 / Cross valid method: THROUGHOUT / σ(F): 1 / ESU R: 0.325 / ESU R Free: 0.271 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29511 752 5 %RANDOM
Rwork0.19612 ---
Obs0.2009 14431 97.9 %-
All-14741 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 39.164 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2--0.64 Å20 Å2
3----0.66 Å2
Refinement stepCycle: LAST / Resolution: 2.15→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2282 0 33 190 2505
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0220.0222375
r_angle_refined_deg2.0761.9763223
r_dihedral_angle_1_deg7.4925283
r_chiral_restr0.1460.2358
r_gen_planes_refined0.0080.021764
r_nbd_refined0.2660.21249
r_xyhbond_nbd_refined0.2030.2182
r_symmetry_vdw_refined0.2460.239
r_symmetry_hbond_refined0.2220.212
r_mcbond_it1.0991.51431
r_mcangle_it1.94122312
r_scbond_it2.9643944
r_scangle_it4.4094.5911
LS refinement shellResolution: 2.15→2.205 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.381 44
Rwork0.248 1042
Obs-1042

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