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

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Basic information

Entry
Database: PDB / ID: 2uzl
TitleCrystal structure of human CDK2 complexed with a thiazolidinone inhibitor
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
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


Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / cellular response to leptin stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / male pronucleus / female pronucleus / cellular response to cocaine ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / cellular response to leptin stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cochlea development / 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 / cellular response to platelet-derived growth factor stimulus / regulation of DNA replication / 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 / cellular response to nitric oxide / Activation of the pre-replicative complex / animal organ regeneration / 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 / Cyclin E associated events during G1/S transition / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / mitotic G1 DNA damage checkpoint signaling / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G1/S transition of mitotic cell cycle / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / cellular senescence / positive regulation of fibroblast proliferation / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / cellular response to hypoxia / Senescence-Associated Secretory Phenotype (SASP) / peptidyl-serine phosphorylation / regulation of gene expression / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / Ub-specific processing proteases / endosome / chromatin remodeling / protein phosphorylation / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding
Similarity search - Function
Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin-like ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / 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
Chem-C94 / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.4 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 1.3Mar 6, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_conn
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval ..._exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Apr 3, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / pdbx_seq_map_depositor_info
Item: _exptl_crystal_grow.temp / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.5Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / 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
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 / _pdbx_entry_details.has_protein_modification

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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
B: CYCLIN A2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,1966
Polymers127,3624
Non-polymers8352
Water7,440413
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0983
Polymers63,6812
Non-polymers4171
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)64,0983
Polymers63,6812
Non-polymers4171
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)211.604, 73.285, 152.367
Angle α, β, γ (deg.)90.00, 129.33, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114B1 - 999
2114D1 - 999

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Components

#1: Protein CELL DIVISION PROTEIN KINASE 2 / P33 PROTEIN KINASE / CYCLIN DEPENDENT KINASE 2


Mass: 34056.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: THR160 PHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: P24941, cyclin-dependent kinase, EC: 2.7.1.37
#2: Protein CYCLIN A2 / CYCLIN-A


Mass: 29624.297 Da / Num. of mol.: 2 / Fragment: RESIDUES 175-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: P20248
#3: Chemical ChemComp-C94 / 4-{5-[(Z)-(2-IMINO-4-OXO-1,3-THIAZOLIDIN-5-YLIDENE)METHYL]FURAN-2-YL}-2-(TRIFLUOROMETHYL)BENZENESULFONAMIDE


Mass: 417.383 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H10F3N3O4S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 413 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsRESIDUES 175 - 432 CYCLIN A2

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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: 3.2 Å3/Da / Density % sol: 61 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: VAPOUR DIFFUSION AT 4 DEG C, 0.1 M HEPES PH 7.0, 1M LITHIUM SULPHATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.939
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 22, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.939 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 61935 / % possible obs: 88.2 % / Observed criterion σ(I): 0 / Redundancy: 2.7 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 7.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 2.4→15 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.875 / SU B: 7.52 / SU ML: 0.175 / Cross valid method: THROUGHOUT / ESU R: 0.347 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.263 3132 5.1 %RANDOM
Rwork0.203 ---
obs0.206 58580 87.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.36 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20.26 Å2
2---1.2 Å20 Å2
3---1.41 Å2
Refinement stepCycle: LAST / Resolution: 2.4→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8920 0 54 413 9387
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229202
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9911.9712510
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.45651102
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.93523.959394
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.683151612
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5561544
X-RAY DIFFRACTIONr_chiral_restr0.1680.21408
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026848
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2080.24256
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3040.26207
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.2472
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2170.257
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2180.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8061.55699
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.40529018
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.89633981
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9514.53492
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
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: B / Ens-ID: 1 / Number: 2077 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
medium positional0.150.5
medium thermal0.532
LS refinement shellResolution: 2.4→2.46 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.37 223
Rwork0.31 3938

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