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- PDB-2uzn: Crystal structure of human CDK2 complexed with a thiazolidinone i... -

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Basic information

Entry
Database: PDB / ID: 2uzn
TitleCrystal structure of human CDK2 complexed with a thiazolidinone inhibitor
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / ATP-BINDING / PHOSPHORYLATION / CDK2 / KINASE / CYCLIN / MITOSIS / CELL CYCLE / CELL DIVISION / NUCLEOTIDE-BINDING / SERINE/THREONINE-PROTEIN KINASE / THIAZOLIDINONE LIGAND
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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / G0 and Early G1 / Telomere Extension By Telomerase / 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 / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / regulation of mitotic cell cycle / cyclin binding / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / 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 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / 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 / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / DNA replication / chromosome, telomeric region / protein phosphorylation / endosome / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
Chem-C96 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRichardson, C.M. / Dokurno, P. / Murray, J.B. / Surgenor, A.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Discovery of a Potent Cdk2 Inhibitor with a Novel Binding Mode, Using Virtual Screening and Initial, Structure-Guided Lead Scoping.
Authors: Richardson, C.M. / Nunns, C.L. / Williamson, D.S. / Parratt, M.J. / Dokurno, P. / Howes, R. / Borgognoni, J. / Drysdale, M.J. / Finch, H. / Hubbard, R.E. / Jackson, P.S. / Kierstan, P. / ...Authors: Richardson, C.M. / Nunns, C.L. / Williamson, D.S. / Parratt, M.J. / Dokurno, P. / Howes, R. / Borgognoni, J. / Drysdale, M.J. / Finch, H. / Hubbard, R.E. / Jackson, P.S. / Kierstan, P. / Lentzen, G. / Moore, J.D. / Murray, J.B. / Simmonite, H. / Surgenor, A.E. / Torrance, C.J.
History
DepositionApr 30, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 13, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,3402
Polymers33,9761
Non-polymers3631
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.591, 71.454, 72.284
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 / CYCLIN DEPENDENT KINASE 2


Mass: 33976.488 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): SF21
References: UniProt: P24941, cyclin-dependent kinase, EC: 2.7.1.37
#2: Chemical ChemComp-C96 / 4-{5-[(1Z)-1-(2-IMINO-4-OXO-1,3-THIAZOLIDIN-5-YLIDENE)ETHYL]-2-FURYL}BENZENESULFONAMIDE


Mass: 363.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13N3O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / 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 Å3/Da / Density % sol: 39 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7
Details: VAPOR DIFFUSION HANGING DROP, ROOM TEMPERATURE, PEG3350, HEPES PH7.2, AMMONIUM ACETATE, pH 7.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU (MSC) / Detector: IMAGE PLATE / Date: Dec 30, 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: 2.1→30 Å / Num. obs: 16796 / % possible obs: 99.5 % / Observed criterion σ(I): 1 / Redundancy: 4.4 % / Rmerge(I) obs: 0.17 / Net I/σ(I): 6.2
Reflection shellResolution: 2.1→2.17 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 2.7 / % possible all: 96

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CrystalCleardata reduction
d*TREKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1B39

1b39


Resolution: 2.3→15 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.871 / SU B: 10.987 / SU ML: 0.266 / Cross valid method: THROUGHOUT / ESU R: 0.48 / ESU R Free: 0.315 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.297 906 7.1 %RANDOM
Rwork0.199 ---
obs0.206 11829 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å20 Å20 Å2
2--1.54 Å20 Å2
3----1.34 Å2
Refinement stepCycle: LAST / Resolution: 2.3→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 24 123 2387
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222323
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8631.9613154
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9165276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.48323.26598
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.72915399
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.511514
X-RAY DIFFRACTIONr_chiral_restr0.1190.2352
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021736
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2460.21165
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.320.21544
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1860.2139
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2990.233
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2150.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9071.51441
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.54222264
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.27331018
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.454.5890
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: 2.3→2.36 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.386 80
Rwork0.241 819

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