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- PDB-2w17: CDK2 in complex with the imidazole pyrimidine amide, compound (S)-8b -

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Basic information

Entry
Database: PDB / ID: 2w17
TitleCDK2 in complex with the imidazole pyrimidine amide, compound (S)-8b
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / KINASE / MITOSIS / CELL CYCLE / SERINE/THREONINE-PROTEIN KINASE / ATP-BINDING / CELL DIVISION / PHOSPHOPROTEIN / PHOSPHORYLATION / NUCLEOTIDE-BINDING
Function / homology
Function and homology information


cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation ...cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / Cajal body / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / male germ cell nucleus / response to organic substance / G1/S transition of mitotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Ras protein signal transduction / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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. ...Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
ACETATE ION / Chem-I19 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsJones, C.D. / Andrews, D.M. / Barker, A.J. / Blades, K. / Daunt, P. / East, S. / Geh, C. / Graham, M.A. / Johnson, K.M. / Loddick, S.A. ...Jones, C.D. / Andrews, D.M. / Barker, A.J. / Blades, K. / Daunt, P. / East, S. / Geh, C. / Graham, M.A. / Johnson, K.M. / Loddick, S.A. / McFarland, H.M. / McGregor, A. / Moss, L. / Rudge, D.A. / Simpson, P.B. / Swain, M.L. / Tam, K.Y. / Tucker, J.A. / Walker, M. / Brassington, C. / Haye, H. / McCall, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: The Discovery of Azd5597, a Potent Imidazole Pyrimidine Amide Cdk Inhibitor Suitable for Intravenous Dosing.
Authors: Jones, C.D. / Andrews, D.M. / Barker, A.J. / Blades, K. / Daunt, P. / East, S. / Geh, C. / Graham, M.A. / Johnson, K.M. / Loddick, S.A. / Mcfarland, H.M. / Mcgregor, A. / Moss, L. / Rudge, D. ...Authors: Jones, C.D. / Andrews, D.M. / Barker, A.J. / Blades, K. / Daunt, P. / East, S. / Geh, C. / Graham, M.A. / Johnson, K.M. / Loddick, S.A. / Mcfarland, H.M. / Mcgregor, A. / Moss, L. / Rudge, D.A. / Simpson, P.B. / Swain, M.L. / Tam, K.Y. / Tucker, J.A. / Walker, M.
History
DepositionOct 15, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 4, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Apr 24, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc ...entity_src_gen / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag

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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)34,5133
Polymers34,0031
Non-polymers5112
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.542, 71.824, 71.771
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 CELL DIVISION PROTEIN KINASE 2 / / CYCLIN DEPENDENT KINASE 2 / P33 PROTEIN KINASE


Mass: 34002.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: ACETYLATION AT N-TERMINAL METHIONINE / Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-I19 / N-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5-fluoro-4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]pyrimidin-2-amine


Mass: 451.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30FN7O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 150 / 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: 2.06 Å3/Da / Density % sol: 40.3 % / Description: NONE
Crystal growpH: 7.5
Details: 8% PEG 3350, 0.1M HEPES PH 7.5, 0.05M AMMONIUM ACETATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Dec 15, 2005 / Details: CONFOCAL MIRRORS (VARIMAX)
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.15→50.77 Å / Num. obs: 15575 / % possible obs: 99.7 % / Observed criterion σ(I): 3 / Redundancy: 3.33 % / Biso Wilson estimate: 31 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 6
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.1 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
CrystalCleardata reduction
CrystalCleardata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL CDK2 STRUCTURE MODEL

Resolution: 2.15→42.93 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.923 / SU B: 18.61 / SU ML: 0.222 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.361 / ESU R Free: 0.265 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS WERE OMITTED FROM THE MODEL, DISORDERED SIDE-CHAINS WERE TRUNCATED TO C-BETA.
RfactorNum. reflection% reflectionSelection details
Rfree0.3001 779 5.06 %RANDOM
Rwork0.2416 ---
obs0.244 15562 99.693 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 39.933 Å2
Baniso -1Baniso -2Baniso -3
1--0.073 Å20 Å20 Å2
2--2.66 Å20 Å2
3----2.587 Å2
Refinement stepCycle: LAST / Resolution: 2.15→42.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 37 150 2396
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222310
X-RAY DIFFRACTIONr_bond_other_d0.0040.021562
X-RAY DIFFRACTIONr_angle_refined_deg1.42723137
X-RAY DIFFRACTIONr_angle_other_deg0.91433814
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4735275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.29723.26192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.17915392
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5931513
X-RAY DIFFRACTIONr_chiral_restr0.0770.2354
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212518
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02453
X-RAY DIFFRACTIONr_nbd_refined0.2140.2480
X-RAY DIFFRACTIONr_nbd_other0.1810.21555
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21120
X-RAY DIFFRACTIONr_nbtor_other0.0880.21109
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.190.2122
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1180.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1760.240
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2350.220
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6051.51403
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.08922266
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.3323907
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.1194.5871
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 9.394→42.93 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.123 11
Rwork0.234 212

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