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- PDB-1h07: CDK2 in complex with a disubstituted 4, 6-bis anilino pyrimidine ... -

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Basic information

Entry
Database: PDB / ID: 1h07
TitleCDK2 in complex with a disubstituted 4, 6-bis anilino pyrimidine CDK4 inhibitor
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / MITOSIS
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 / cyclin-dependent protein kinase activity / G2 Phase / 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 / cyclin-dependent protein kinase activity / G2 Phase / 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 / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / cellular response to nitric oxide / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / 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 / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / protein domain specific binding / protein phosphorylation / cell division / protein serine/threonine kinase activity / protein serine kinase activity / DNA repair / DNA-templated transcription / centrosome / 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
: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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
Chem-MFP / Chem-MFQ / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsBeattie, 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.
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.
History
DepositionJun 11, 2002Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 11, 2003Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)35,0253
Polymers34,0031
Non-polymers1,0232
Water3,603200
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.323, 71.543, 72.550
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 / 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-MFP / ((2-BROMO-4-METHYLPHENYL){6-[(4-{[(2R)-3-(DIMETHYLAMINO)-2-HYDROXYPROPYL]OXY}PHENYL)AMINO]PYRIMIDIN-4-YL}AMINO)ACETONITRILE


Mass: 511.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27BrN6O2
#3: Chemical ChemComp-MFQ / ((2-BROMO-4-METHYLPHENYL){6-[(4-{[(2S)-3-(DIMETHYLAMINO)-2-HYDROXYPROPYL]OXY}PHENYL)AMINO]PYRIMIDIN-4-YL}AMINO)ACETONITRILE


Mass: 511.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27BrN6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 39 %
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: SRS / Beamline: PX9.6 / Wavelength: 0.87
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: May 15, 1998
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87 Å / Relative weight: 1
ReflectionResolution: 1.85→32.35 Å / Num. obs: 21455 / % possible obs: 88.8 % / Redundancy: 2.5 % / Biso Wilson estimate: 15.9 Å2 / Rmerge(I) obs: 0.096 / Net I/σ(I): 10.2
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.191 / Mean I/σ(I) obs: 4.7 / % possible all: 71.6
Reflection
*PLUS
Highest resolution: 1.85 Å / % possible obs: 87.7 % / Num. measured all: 53065 / Rmerge(I) obs: 0.096

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Processing

Software
NameVersionClassification
CNX2000.1refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→32.35 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1361929.81 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: RESIDUES 37 - 43 AND 151 - 154 ARE NOT VISIBLE IN THE ELECTRON DENSITY MAP.
RfactorNum. reflection% reflectionSelection details
Rfree0.235 1057 4.9 %RANDOM
Rwork0.21 ---
obs-21433 87.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 56.3383 Å2 / ksol: 0.383733 e/Å3
Displacement parametersBiso mean: 23.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å20 Å20 Å2
2--2.81 Å20 Å2
3----2.74 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.21 Å
Luzzati d res low-25 Å
Luzzati sigma a0.08 Å-0.02 Å
Refinement stepCycle: LAST / Resolution: 1.85→32.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2248 0 66 200 2514
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.4
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.85
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.411.5
X-RAY DIFFRACTIONc_mcangle_it2.22
X-RAY DIFFRACTIONc_scbond_it2.332
X-RAY DIFFRACTIONc_scangle_it3.252.5
LS refinement shellResolution: 1.85→1.96 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.242 154 5.2 %
Rwork0.221 2788 -
obs--73.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
Refinement
*PLUS
% reflection Rfree: 5 % / Rfactor Rwork: 0.21
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.85

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