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- PDB-2wih: STRUCTURE OF CDK2-CYCLIN A WITH PHA-848125 -

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Basic information

Entry
Database: PDB / ID: 2wih
TitleSTRUCTURE OF CDK2-CYCLIN A WITH PHA-848125
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsTRANSFERASE / CELL CYCLE / ATP-BINDING / POLYMORPHISM / PHOSPHORYLATION / NUCLEOTIDE-BINDING / CELL DIVISION / SERINE/THREONINE-PROTEIN 2 KINASE / PHOSPHOPROTEIN / SERINE/THREONINE-PROTEIN KINASE / MITOSIS
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 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / 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 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / cochlea development / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cellular response to platelet-derived growth factor stimulus / 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 / 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 / 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 / animal organ regeneration / 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 / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / 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 / positive regulation of fibroblast proliferation / cellular senescence / 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) / 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 / Ub-specific processing proteases / 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 / protein kinase binding / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion 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-P48 / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.5 Å
AuthorsBrasca, M.G. / Amboldi, N. / Ballinari, D. / Cameron, A.D. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / Dalessio, R. ...Brasca, M.G. / Amboldi, N. / Ballinari, D. / Cameron, A.D. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / Dalessio, R. / Fiorentini, F. / Isacchi, A. / Mercurio, C. / Moretti, W. / Panzeri, A. / Pastori, W. / Pevarello, P. / Quartieri, F. / Roletto, F. / Traquandi, G. / Vianello, P. / Vulpetti, A. / Ciomei, M.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Identification of N,1,4,4-Tetramethyl-8-{[4-(4-Methylpiperazin-1-Yl)Phenyl]Amino}-4,5-Dihydro-1H-Pyrazolo[4,3-H]Quinazoline-3-Carboxamide (Pha-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor.
Authors: Brasca, M.G. / Amboldi, N. / Ballinari, D. / Cameron, A.D. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / Dalessio, R. / Fiorentini, F. / Isacchi, A. / Mercurio, C. / ...Authors: Brasca, M.G. / Amboldi, N. / Ballinari, D. / Cameron, A.D. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / Dalessio, R. / Fiorentini, F. / Isacchi, A. / Mercurio, C. / Moretti, W. / Panzeri, A. / Pastori, W. / Pevarello, P. / Quartieri, F. / Roletto, F. / Traquandi, G. / Vianello, P. / Vulpetti, A. / Ciomei, M.
History
DepositionMay 13, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_scientific_name ..._entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain / _pdbx_database_status.recvd_author_approval

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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)132,0797
Polymers131,0624
Non-polymers1,0173
Water3,855214
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9913
Polymers65,5312
Non-polymers4611
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-10.5 kcal/mol
Surface area23500 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0874
Polymers65,5312
Non-polymers5572
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3230 Å2
ΔGint-22.3 kcal/mol
Surface area23010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)183.000, 183.000, 213.560
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222

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Components

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


Mass: 35251.883 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein CYCLIN-A2 / CYCLIN A / CYCLIN A2


Mass: 30278.967 Da / Num. of mol.: 2 / Fragment: C-TERMINAL PORTION, RESIDUES 173-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX6P / Production host: ESCHERICHIA COLI BL21 (bacteria) / References: UniProt: P20248
#3: Chemical ChemComp-P48 / N,1,4,4-TETRAMETHYL-8-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE


Mass: 460.575 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N8O
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 4 Å3/Da / Density % sol: 64 % / Description: NONE
Crystal growDetails: 20% AMMONIUM SULPHATE, 1M KCL, 40MM HEPES PH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.97
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 28, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 72932 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 7 % / Biso Wilson estimate: 45.6 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 16.1
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 0 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 3.7 / % possible all: 100

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Processing

Software
NameClassification
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.5→29.96 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 4212802.71 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: THERE IS A FEATURE IN THE ELECTRON DENSITY MAP ATTACHED TO ASP 28 OF BOTH CDK2 MOLECULES THAT COULD NOT BE ASSIGNED TO ANY MOLECULE IN THE CRYSTALLISATION MIXTURE. THIS HAS BEEN MODELLED BY WATER MOLECULES.
RfactorNum. reflection% reflectionSelection details
Rfree0.25 3685 5.1 %RANDOM
Rwork0.213 ---
obs0.215 72889 99.6 %-
all-72889 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 24.46 Å2 / ksol: 0.32 e/Å3
Displacement parametersBiso mean: 48.5 Å2
Baniso -1Baniso -2Baniso -3
1-5.95 Å27.54 Å20 Å2
2--5.95 Å20 Å2
3----11.91 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.32 Å
Luzzati d res low-5 Å
Luzzati sigma a0.38 Å0.32 Å
Refinement stepCycle: LAST / Resolution: 2.5→29.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8976 0 73 214 9263
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_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.69
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.471.5
X-RAY DIFFRACTIONc_mcangle_it2.52
X-RAY DIFFRACTIONc_scbond_it2.192
X-RAY DIFFRACTIONc_scangle_it3.352.5
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.014 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.335 611 5.1 %
Rwork0.293 11358 -
obs--99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3125.PAR125.TOP

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