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- PDB-3ej1: CDK2/CyclinA complexed with a pyrazolopyridazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ej1
TitleCDK2/CyclinA complexed with a pyrazolopyridazine inhibitor
Components
  • Cell division protein kinase 2
  • Cyclin-A2
KeywordsTransferase/Cell cycle / cdk / cyclin / kinase / ATP-binding / Cell cycle / Cell division / Mitosis / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Transferase / Nucleus / Transferase-Cell cycle COMPLEX
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-5BP / Cyclin-A2 / Uncharacterized protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.22 Å
AuthorsStevens, K. / Reno, M. / Alberti, J. / Price, D. / Kane-Carson, L. / Knick, V. / Shewchuk, L. / Hassell, A. / Veal, J. / Peel, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.
Authors: Stevens, K.L. / Reno, M.J. / Alberti, J.B. / Price, D.J. / Kane-Carson, L.S. / Knick, V.B. / Shewchuk, L.M. / Hassell, A.M. / Veal, J.M. / Davis, S.T. / Griffin, R.J. / Peel, M.R.
History
DepositionSep 17, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Jul 24, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)128,1936
Polymers127,6884
Non-polymers5052
Water00
1
A: Cell division protein kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0963
Polymers63,8442
Non-polymers2521
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3010 Å2
ΔGint-13 kcal/mol
Surface area23940 Å2
MethodPISA
2
C: Cell division protein kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0963
Polymers63,8442
Non-polymers2521
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-15 kcal/mol
Surface area23550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)183.776, 183.776, 214.045
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D
12A
22C
13A
23C

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1116B172 - 435
2116D172 - 435
1126A1 - 82
2126C1 - 82
1136A84 - 290
2136C84 - 290

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Cell division protein kinase 2 / p33 protein kinase


Mass: 33976.488 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2 / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A


Mass: 29867.512 Da / Num. of mol.: 2 / Fragment: UNP residues 113-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Plasmid: pET21 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P20248
#3: Chemical ChemComp-5BP / N-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine


Mass: 252.275 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H12N6

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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: 4.09 Å3/Da / Density % sol: 69.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 1.5 M sodium acetate, 100 mM sodium cacodylate, pH 6.7, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: May 28, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.22→160.13 Å / Num. all: 32959 / Num. obs: 32959 / % possible obs: 98 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 13.9 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 22
Reflection shellResolution: 3.22→3.3 Å / Redundancy: 12.2 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 2.1 / Num. unique all: 2297 / % possible all: 95

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FVV

1fvv


Resolution: 3.22→160.13 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.925 / SU B: 46.661 / SU ML: 0.353 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R Free: 0.441 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25887 1737 5 %RANDOM
Rwork0.219 ---
all0.22099 32959 --
obs0.22099 32959 98.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 69.353 Å2
Baniso -1Baniso -2Baniso -3
1-3.85 Å21.93 Å20 Å2
2--3.85 Å20 Å2
3----5.78 Å2
Refinement stepCycle: LAST / Resolution: 3.22→160.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8788 0 38 0 8826
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0229053
X-RAY DIFFRACTIONr_angle_refined_deg1.1121.98212295
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.14951098
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.37923.861373
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.099151580
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5861543
X-RAY DIFFRACTIONr_chiral_restr0.0720.21402
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026758
X-RAY DIFFRACTIONr_nbd_refined0.1950.24394
X-RAY DIFFRACTIONr_nbtor_refined0.3030.26199
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1340.2237
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2050.240
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1460.27
X-RAY DIFFRACTIONr_mcbond_it01.55647
X-RAY DIFFRACTIONr_mcangle_it028966
X-RAY DIFFRACTIONr_scbond_it033814
X-RAY DIFFRACTIONr_scangle_it04.53323
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1B2047loose positional0.315
2A609loose positional0.365
3A1645loose positional0.325
1B2047loose thermal010
2A609loose thermal010
3A1645loose thermal010
LS refinement shellResolution: 3.22→3.302 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 119 -
Rwork0.297 2297 -
obs-2297 95.16 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.66370.5681-0.39351.70951.80793.5538-0.014-0.2748-0.04190.4051-0.13790.0370.16820.06980.1519-0.1473-0.03410.0402-0.2182-0.0369-0.4773-19.989214.88119.482
20.96460.43630.96232.77151.50646.899-0.01150.0458-0.2041-0.0157-0.29710.58890.4894-0.03180.3086-0.1638-0.03560.101-0.2424-0.34680.1123-37.973175.5973.753
34.2838-1.315-0.61273.1210.14542.6123-0.28390.0623-0.25790.4301-0.13170.29520.059-0.27720.4157-0.1652-0.11930.222-0.175-0.2533-0.372-48.329198.99113.785
41.9812-0.2007-0.31582.4149-1.13593.9743-0.02090.23040.1762-0.3345-0.20750.4995-0.11340.00070.2284-0.119-0.0916-0.0023-0.2472-0.1945-0.2411-20.657203.42673.088
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 298
2X-RAY DIFFRACTION2C1 - 297
3X-RAY DIFFRACTION3B175 - 432
4X-RAY DIFFRACTION4D176 - 432

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