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- PDB-2wip: STRUCTURE OF CDK2-CYCLIN A COMPLEXED WITH 8-ANILINO-1-METHYL-4,5-... -

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Entry
Database: PDB / ID: 2wip
TitleSTRUCTURE OF CDK2-CYCLIN A COMPLEXED WITH 8-ANILINO-1-METHYL-4,5-DIHYDRO- 1H-PYRAZOLO[4,3-H] QUINAZOLINE-3-CARBOXYLIC ACID
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsTRANSFERASE / CELL CYCLE / ATP-BINDING / POLYMORPHISM / PHOSPHORYLATION / NUCLEOTIDE-BINDING / SERINE/THREONINE-PROTEIN 2 KINASE / SERINE/THREONINE-PROTEIN KINASE / CELL DIVISION / PHOSPHOPROTEIN / PROTEIN KINASE / KINASE / CYCLIN / NUCLEUS / MITOSIS / CYTOPLASM
Function / homology
Function and homology information


G2 Phase / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cyclin A2-CDK2 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / p53-Dependent G1 DNA Damage Response / mitotic cell cycle phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Regulation of APC/C activators between G1/S and early anaphase ...G2 Phase / Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cyclin A2-CDK2 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / p53-Dependent G1 DNA Damage Response / mitotic cell cycle phase transition / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Regulation of APC/C activators between G1/S and early anaphase / cellular response to leptin stimulus / male pronucleus / Telomere Extension By Telomerase / G0 and Early G1 / female pronucleus / response to glucagon / cellular response to cocaine / cellular response to nitric oxide / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cochlea development / cellular response to platelet-derived growth factor stimulus / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / regulation of DNA replication / animal organ regeneration / post-translational protein modification / cellular response to estradiol stimulus / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Orc1 removal from chromatin / G1/S transition of mitotic cell cycle / G2/M transition of mitotic cell cycle / positive regulation of fibroblast proliferation / Regulation of TP53 Degradation / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / Ub-specific processing proteases / protein domain specific binding / cell division / centrosome / DNA-templated transcription / positive regulation of DNA-templated transcription / protein kinase binding / nucleoplasm / nucleus / cytoplasm / cytosol
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 / Replication initiator protein RctB, central region / RctB, helix turn helix domain / Vibrionales, replication initiator protein RctB, central region / RctB helix turn helix 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 / Protein kinase domain / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-P49 / Cyclin-A2 / Uncharacterized protein
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.8 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. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / D'Alessio, R. / Fiorentini, F. / Isacchi, A. / Mercurio, C. / ...Authors: Brasca, M.G. / Amboldi, N. / Ballinari, D. / Cameron, A. / Casale, E. / Cervi, G. / Colombo, M. / Colotta, F. / Croci, V. / D'Alessio, 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 14, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2009Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2012Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Refinement description / Version format compliance
Revision 1.2Apr 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
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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_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
B: CYCLIN-A2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,8007
Polymers131,0624
Non-polymers7393
Water3,099172
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8523
Polymers65,5312
Non-polymers3211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2970 Å2
ΔGint-11 kcal/mol
Surface area23450 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9484
Polymers65,5312
Non-polymers4172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-21.6 kcal/mol
Surface area23060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)184.185, 184.185, 215.005
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-P49 / 1-methyl-8-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid


Mass: 321.333 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N5O2
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O
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: 69 % / Description: NONE
Crystal growDetails: 20% AMMONIUM SULPHATE, 1M KCL, 40MM HEPES PH 7

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.5418
DetectorType: RIGAKU R-AXIS IV / Detector: IMAGE PLATE / Date: Apr 2, 2002 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 50354 / % possible obs: 94.1 % / Observed criterion σ(I): 0 / Redundancy: 6 % / Biso Wilson estimate: 50.4 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 23.8
Reflection shellResolution: 2.8→2.85 Å / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 6.2 / % possible all: 95

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Processing

Software
NameVersionClassification
CNSNULLrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.8→28.4 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 3178115.1 / Data cutoff low absF: 0 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.258 1015 2 %RANDOM
Rwork0.221 ---
obs0.221 50220 94.1 %-
Solvent computationBsol: 39.8044 Å2 / ksol: 0.340149 e/Å3
Displacement parametersBiso mean: 48.2 Å2
Baniso -1Baniso -2Baniso -3
1-5.27 Å212 Å20 Å2
2--5.27 Å20 Å2
3----10.54 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.44 Å0.36 Å
Luzzati d res low-5 Å
Luzzati sigma a0.48 Å0.41 Å
Refinement stepCycle: LAST / Resolution: 2.8→28.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8887 0 53 172 9112
Refine LS restraints
Refine-IDTypeDev ideal
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_d20.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 2.8→2.98 Å / Rfactor Rfree error: 0.026 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.343 175 2.1 %
Rwork0.294 8125 -
obs--95.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3290.PAR290.TOP

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