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- PDB-2wxv: Structure of CDK2-CYCLIN A with a Pyrazolo(4,3-h) quinazoline-3- ... -

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Basic information

Entry
Database: PDB / ID: 2wxv
TitleStructure of CDK2-CYCLIN A with a Pyrazolo(4,3-h) quinazoline-3- carboxamide inhibitor
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsTRANSFERASE / NUCLEOTIDE-BINDING / SERINE/THREONINE-PROTEIN KINASE / CELL CYCLE / KINASE / CYCLIN
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-WXV / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsTraquandi, G. / Ciomei, M. / Ballinari, D. / Casale, E. / Colombo, N. / Croci, V. / Fiorentini, F. / Isacchi, A. / Longo, A. / Mercurio, C. ...Traquandi, G. / Ciomei, M. / Ballinari, D. / Casale, E. / Colombo, N. / Croci, V. / Fiorentini, F. / Isacchi, A. / Longo, A. / Mercurio, C. / Panzeri, A. / Pastori, W. / Pevarello, P. / Volpi, D. / Roussel, P. / Vulpetti, A. / Brasca, M.G.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Identification of Potent Pyrazolo[4,3-H]Quinazoline-3-Carboxamides as Multi-Cyclin-Dependent Kinase Inhibitors.
Authors: Traquandi, G. / Ciomei, M. / Ballinari, D. / Casale, E. / Colombo, N. / Croci, V. / Fiorentini, F. / Isacchi, A. / Longo, A. / Mercurio, C. / Panzeri, A. / Pastori, W. / Pevarello, P. / ...Authors: Traquandi, G. / Ciomei, M. / Ballinari, D. / Casale, E. / Colombo, N. / Croci, V. / Fiorentini, F. / Isacchi, A. / Longo, A. / Mercurio, C. / Panzeri, A. / Pastori, W. / Pevarello, P. / Volpi, D. / Roussel, P. / Vulpetti, A. / Brasca, M.G.
History
DepositionNov 10, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 23, 2010Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2011Group: Database references / Derived calculations ...Database references / Derived calculations / 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

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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)131,9937
Polymers131,0624
Non-polymers9313
Water2,522140
1
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0444
Polymers65,5312
Non-polymers5142
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3140 Å2
ΔGint-20.9 kcal/mol
Surface area23580 Å2
MethodPISA
2
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,9483
Polymers65,5312
Non-polymers4171
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2940 Å2
ΔGint-9.7 kcal/mol
Surface area23920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)185.513, 185.513, 215.180
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 A2 / CYCLIN-A


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) / Production host: ESCHERICHIA COLI BL21 (bacteria) / References: UniProt: P20248
#3: Chemical ChemComp-WXV / N,1-DIMETHYL-8-{[1-(METHYLSULFONYL)PIPERIDIN-4-YL]AMINO}-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE


Mass: 417.485 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H23N7O3S
#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.: 140 / Source method: isolated from a natural source / Formula: H2O
Sequence details5 AMINO ACIDS EXTRA AT THE N-TERMINUS DUE TO CLONING

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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: 4.15 Å3/Da / Density % sol: 70 % / Description: NONE
Crystal growDetails: 20% AMMONIUM SULPHATE, 1M KCL, 40MM HEPES PH7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.979
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. obs: 66956 / % possible obs: 99.2 % / Observed criterion σ(I): 0 / Redundancy: 4 % / Biso Wilson estimate: 45.3 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 13
Reflection shellResolution: 2.6→2.69 Å / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2.3 / % possible all: 99

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→29.8 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 4202525.63 / Data cutoff low absF: 0 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.243 3378 5 %RANDOM
Rwork0.211 ---
obs0.211 66915 99.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 34.1021 Å2 / ksol: 0.326522 e/Å3
Displacement parametersBiso mean: 51 Å2
Baniso -1Baniso -2Baniso -3
1-5.82 Å29.78 Å20 Å2
2--5.82 Å20 Å2
3----11.64 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.39 Å0.34 Å
Luzzati d res low-5 Å
Luzzati sigma a0.47 Å0.41 Å
Refinement stepCycle: LAST / Resolution: 2.6→29.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8984 0 63 140 9187
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_deg1
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.7
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: 2.6→2.76 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.347 556 5.1 %
Rwork0.315 10390 -
obs--99.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3801.PAR801.TOP

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