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- PDB-2bpm: STRUCTURE OF CDK2-CYCLIN A WITH PHA-630529 -

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Entry
Database: PDB / ID: 2bpm
TitleSTRUCTURE OF CDK2-CYCLIN A WITH PHA-630529
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
KeywordsTRANSFERASE / PROTEIN KINASE / SERINE/THREONINE-PROTEIN KINASE / PHOSPHORYLATION / CELL DIVISION / CYCLIN
Function / homology
Function and homology information


Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / G0 and Early G1 / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of APC/C activators between G1/S and early anaphase / Activation of ATR in response to replication stress / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / DNA Damage/Telomere Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Ub-specific processing proteases ...Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / G0 and Early G1 / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of APC/C activators between G1/S and early anaphase / Activation of ATR in response to replication stress / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / DNA Damage/Telomere Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Ub-specific processing proteases / Factors involved in megakaryocyte development and platelet production / Meiotic recombination / PTK6 Regulates Cell Cycle / Cyclin A:Cdk2-associated events at S phase entry / p53-Dependent G1 DNA Damage Response / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / Processing of DNA double-strand break ends / CDK-mediated phosphorylation and removal of Cdc6 / Activation of the pre-replicative complex / Orc1 removal from chromatin / G2 Phase / Regulation of TP53 Degradation / Regulation of TP53 Activity through Phosphorylation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to luteinizing hormone stimulus / cellular response to cocaine / cell cycle G1/S phase transition / male pronucleus / female pronucleus / cellular response to insulin-like growth factor stimulus / cellular response to leptin stimulus / response to glucagon / cochlea development / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to platelet-derived growth factor stimulus / regulation of mitotic nuclear division / regulation of DNA replication / regulation of cyclin-dependent protein serine/threonine kinase activity / cyclin E1-CDK2 complex / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-dependent DNA replication initiation / Y chromosome / cyclin-dependent protein kinase activity / X chromosome / histone phosphorylation / centrosome duplication / centriole replication / ec:2.7.11.22: / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / Cajal body / cellular response to nitric oxide / mitotic G1 DNA damage checkpoint / cyclin binding / positive regulation of cell cycle / regulation of gene silencing / potassium ion transport / meiotic cell cycle / cellular response to estradiol stimulus / chromosome, telomeric region / animal organ regeneration / G1/S transition of mitotic cell cycle / positive regulation of fibroblast proliferation / regulation of G2/M transition of mitotic cell cycle / anaphase-promoting complex-dependent catabolic process / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / cellular response to hypoxia / mitotic cell cycle / Ras protein signal transduction / transcription factor complex / G2/M transition of mitotic cell cycle / regulation of signal transduction by p53 class mediator / DNA replication / endosome / peptidyl-serine phosphorylation / protein deubiquitination / centrosome / cell division / DNA repair / protein domain specific binding / viral process / protein serine/threonine kinase activity / protein phosphorylation / positive regulation of cell population proliferation / protein kinase binding / positive regulation of transcription, DNA-templated / magnesium ion binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Serine/threonine-protein kinase, active site / Protein kinase-like domain superfamily / Cyclin-like / Protein kinase, ATP binding site / Protein kinase domain profile. / Cyclins signature. / Cyclin-A, N-terminal / Cyclin-like superfamily / Serine/Threonine protein kinases active-site signature. / Protein kinases ATP-binding region signature. ...Serine/threonine-protein kinase, active site / Protein kinase-like domain superfamily / Cyclin-like / Protein kinase, ATP binding site / Protein kinase domain profile. / Cyclins signature. / Cyclin-A, N-terminal / Cyclin-like superfamily / Serine/Threonine protein kinases active-site signature. / Protein kinases ATP-binding region signature. / N-terminal region of cyclin_N / Cyclin, C-terminal domain / Cyclin, N-terminal domain / Cyclin / Protein kinase domain / Cyclin, C-terminal domain / Cyclin, N-terminal / Protein kinase domain
Cyclin-A2 / Cyclin-dependent kinase 2
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsCameron, A. / Fogliatto, G. / Pevarello, P. / Brasca, M.G. / Orsini, P. / Traquandi, G. / Longo, A. / Nesi, M. / Orzi, F. / Piutti, C. / Sansonna, P. / Varasi, M. / Vulpetti, A. / Roletto, F. / Alzani, R. / Ciomei, M. / Albanese, C. / Pastori, W. / Marsiglio, A. / Pesenti, E. / Fiorentini, F. / Bischoff, J.R. / Mercurio, C.
CitationJournal: J.Med.Chem. / Year: 2005
Title: 3-Aminopyrazole Inhibitors of Cdk2-Cyclin a as Antitumor Agents. 2. Lead Optimization
Authors: Pevarello, P. / Brasca, M.G. / Orsini, P. / Traquandi, G. / Longo, A. / Nesi, M. / Orzi, F. / Piutti, C. / Sansonna, P. / Varasi, M. / Cameron, A. / Vulpetti, A. / Roletto, F. / Alzani, R. / Ciomei, M. / Albanese, C. / Pastori, W. / Marsiglio, A. / Pesenti, E. / Fiorentini, F. / Bischoff, J.R. / Mercurio, C.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Apr 21, 2005 / Release: Dec 8, 2005
RevisionDateData content typeGroupCategoryItemProviderType
1.0Dec 8, 2005Structure modelrepositoryInitial release
1.1May 8, 2011Structure modelVersion format compliance
1.2Jul 13, 2011Structure modelVersion format compliance
1.3Apr 3, 2019Structure modelData collection / Other / Source and taxonomyentity_src_gen / pdbx_database_proc / pdbx_database_status_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

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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)131,9298
Polymers131,0624
Non-polymers8674
Water7,458414
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9644
Polymers65,5312
Non-polymers4332
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)65,9644
Polymers65,5312
Non-polymers4332
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
γ
α
β
Length a, b, c (Å)183.614, 183.614, 214.129
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222
Noncrystallographic symmetry (NCS)NCS oper:

Code: given

IDMatrixVector
1(-0.249, -0.88, 0.405), (-0.868, 0.016, -0.497), (0.431, -0.475, -0.767)96.06332, 213.43822, 273.71194
2(-0.245, -0.887, 0.392), (-0.865, 0.017, -0.501), (0.438, -0.462, -0.771)99.31666, 213.85143, 271.3429

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Components

#1: Protein/peptide 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/peptide CYCLIN A2 / / CYCLIN A


Mass: 30278.967 Da / Num. of mol.: 2 / Fragment: RESIDUES 174-432 (C-TERMINAL PORTION)
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-529 / (2S)-N-[(3Z)-5-CYCLOPROPYL-3H-PYRAZOL-3-YLIDENE]-2-[4-(2-OXOIMIDAZOLIDIN-1-YL)PHENYL]PROPANAMIDE


Mass: 337.376 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N5O2
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4 / Sulfate
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 414 / Source method: isolated from a natural source / Formula: H2O / Water
Compound detailsFUNCTION: CELL DIVISION PROTEIN KINASE 2 HAS A POSSIBLE INVOLVEMENT IN THE CONTROL OF THE CELL ...FUNCTION: CELL DIVISION PROTEIN KINASE 2 HAS A POSSIBLE INVOLVEMENT IN THE CONTROL OF THE CELL CYCLE. CYCLIN A2 IS ESSENTIAL FOR THE CONTROL OF THE CELL CYCLE AT THE G1/S (START) AND THE G2/M (MITOSIS) TRANSITIONS
Sequence details5 AMINO ACIDS EXTRA AT THE N-TERMINUS DUE TO CLONING PROTOCOL

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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 %
Crystal growpH: 7 / Details: 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: ID14-1 / Wavelength: 0.934
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 28, 2004 / Details: SAGITALLY FOCUSING, MULTILAYER
RadiationMonochromator: DIAMOND (111), GE(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 82891 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 8 % / Biso Wilson estimate: 38.9 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 16.87
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 7 % / Rmerge(I) obs: 0.04 / Mean I/σ(I) obs: 3.8 / % possible all: 98.8

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Processing

Software
NameVersionClassification
CNX2002refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1VYW
Resolution: 2.4→29.76 Å / Rfactor Rfree error: 0.007 / Isotropic thermal model: BFACTOR_MODEL / Cross valid method: THROUGHOUT / σ(F): 0
Details: BULK SOLVENT MODEL USED. 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
Rfree0.271 1681 2 %RANDOM
Rwork0.229 ---
Obs-82675 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.8379 Å2 / ksol: 0.336201 e/Å3
Displacement parametersBiso mean: 51.6 Å2
Baniso -1Baniso -2Baniso -3
1-6.1 Å27.62 Å20 Å2
2--6.1 Å20 Å2
3----12.2 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.34 Å
Luzzati d res low-5 Å
Luzzati sigma a0.4 Å0.36 Å
Refinement stepCycle: LAST / Resolution: 2.4→29.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8978 0 60 414 9452
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal target
c_bond_d0.007
c_bond_d_na
c_bond_d_prot
c_angle_d
c_angle_d_na
c_angle_d_prot
c_angle_deg1.3
c_angle_deg_na
c_angle_deg_prot
c_dihedral_angle_d20.9
c_dihedral_angle_d_na
c_dihedral_angle_d_prot
c_improper_angle_d0.85
c_improper_angle_d_na
c_improper_angle_d_prot
c_mcbond_it1.61.5
c_mcangle_it2.72
c_scbond_it2.32
c_scangle_it3.62.5
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6 /
Rfactor% reflection
Rfree0.35 2.1 %
Rwork0.321 -
Obs-98 %
Xplor fileSerial no: 1 / Param file: PROTEIN_TPO.PARAM / Topol file: 529.TOP

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