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- PDB-4fx3: Crystal Structure of the CDK2/Cyclin A complex with oxindole inhibitor -

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Basic information

Entry
Database: PDB / ID: 4fx3
TitleCrystal Structure of the CDK2/Cyclin A complex with oxindole inhibitor
Components
  • Cyclin-A2
  • Cyclin-dependent kinase 2
Keywordstransferase/transferase inhibitor / COMPLEX (TRANSFERASE-CYCLIN) / transferase-transferase inhibitor 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-60K / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / Cyclin-A2 / Uncharacterized protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsKang, Y.N. / Stuckey, J.A.
CitationJournal: To be Published
Title: Crystal Structure of the CDK2/Cyclin A complex with oxindole inhibitor
Authors: Kang, Y.N. / Stuckey, J.A.
History
DepositionJul 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 1.2Sep 13, 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: Cyclin-dependent kinase 2
B: Cyclin-A2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,3859
Polymers127,2024
Non-polymers1,1835
Water2,774154
1
A: Cyclin-dependent kinase 2
B: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2705
Polymers63,6012
Non-polymers6693
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3690 Å2
ΔGint-15 kcal/mol
Surface area23090 Å2
MethodPISA
2
C: Cyclin-dependent kinase 2
D: Cyclin-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,1154
Polymers63,6012
Non-polymers5152
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-15 kcal/mol
Surface area23070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.661, 163.623, 72.609
Angle α, β, γ (deg.)90.000, 106.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Cyclin-dependent kinase 2 / 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, CDKN2 / Plasmid: pFB1 / Cell line (production host): high-five / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein Cyclin-A2 / Cyclin-A


Mass: 29624.297 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 175-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCN1, CCNA, CCNA2, Cyclin A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P20248
#3: Chemical ChemComp-60K / (3Z)-2-oxo-3-[2-(4-sulfamoylphenyl)hydrazinylidene]-2,3-dihydro-1H-indole-5-carboxylic acid


Mass: 360.345 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H12N4O5S
#4: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O2S2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / 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: 3.16 Å3/Da / Density % sol: 61.07 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 22% polyacrylic acid 5100, 0.1M HEPES, 0.02M MgCl2, vapor diffusion, sitting drop, temperature 293.15K, pH 7.5, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 13, 2011 / Details: mirrors
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 40559 / % possible obs: 99.5 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.118 / Χ2: 1.109 / Net I/σ(I): 5.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.75-2.83.60.46520090.807199.4
2.8-2.853.60.43320150.795199.6
2.85-2.93.60.38120230.786199.7
2.9-2.963.60.37120490.899199.6
2.96-3.033.60.30320310.906199.6
3.03-3.13.50.26819650.943199.6
3.1-3.173.50.23520570.962199.8
3.17-3.263.60.2220240.987199.7
3.26-3.363.50.19320411.074199.7
3.36-3.463.50.15820191.129199.8
3.46-3.593.50.14120141.19199.7
3.59-3.733.50.12520391.285199.5
3.73-3.93.60.11120231.333199.5
3.9-4.113.50.10420161.396199.3
4.11-4.363.50.09120271.42199.3
4.36-4.73.50.08520381.404199.4
4.7-5.173.50.08320211.301199.8
5.17-5.923.60.08420541.173199.8
5.92-7.463.50.07820271.187199.1
7.46-503.40.06120671.236198.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.1refinement
PDB_EXTRACT3.11data extraction
MD2data collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
BUSTER2.11.1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FIN

1fin


Resolution: 2.75→42.91 Å / Cor.coef. Fo:Fc: 0.905 / Cor.coef. Fo:Fc free: 0.875 / Occupancy max: 1 / Occupancy min: 0 / SU R Cruickshank DPI: 0.773 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2396 2038 5.03 %RANDOM
Rwork0.1899 ---
obs0.1924 40541 97.86 %-
Displacement parametersBiso max: 133.49 Å2 / Biso mean: 51.0173 Å2 / Biso min: 18.2 Å2
Baniso -1Baniso -2Baniso -3
1--11.641 Å20 Å2-12.734 Å2
2---3.4949 Å20 Å2
3---15.1358 Å2
Refine analyzeLuzzati coordinate error obs: 0.345 Å
Refinement stepCycle: LAST / Resolution: 2.75→42.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8835 0 74 154 9063
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4187SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes198HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1378HARMONIC5
X-RAY DIFFRACTIONt_it9169HARMONIC20
X-RAY DIFFRACTIONt_chiral_improper_torsion1187SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact10583SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9169HARMONIC20.011
X-RAY DIFFRACTIONt_angle_deg12488HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion2.98
LS refinement shellResolution: 2.74→2.81 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2664 129 5.51 %
Rwork0.225 2213 -
all0.2275 2342 -
obs--97.86 %
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)
10.65780.0895-0.00921.7910.21640.4806-0.0253-0.07380.04330.00010.03670.10680.05190.0878-0.0113-0.03040.0380.077-0.09930.014-0.0401-1.136414.230537.2831
21.08280.33240.1790.49420.05121.70510.0013-0.11210.0037-0.10830.08280.0963-0.06260.3059-0.0841-0.00250.01060.0921-0.0763-0.0323-0.078716.646510.00799.6261
30.5532-0.1529-0.05621.50330.16650.9118-0.02290.0078-0.0047-0.06090.1010.04660.04170.0327-0.07810.0018-0.03250.0396-0.1089-0.0033-0.07079.5191-37.55253.1991
41.4321-0.4293-0.2420.7666-0.02730.6708-0.066-0.07220.03980.05340.07890.08250.1160.1959-0.0129-0.01780.02110.0208-0.0556-0.0152-0.05969.1617-32.833235.9279
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - 298}A1 - 298
2X-RAY DIFFRACTION2{B|176 - 432}B176 - 432
3X-RAY DIFFRACTION3{C|1 - 298}C1 - 298
4X-RAY DIFFRACTION4{D|175 - 432}D175 - 432

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