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- PDB-1p5e: The structure of phospho-CDK2/cyclin A in complex with the inhibi... -

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Basic information

Entry
Database: PDB / ID: 1p5e
TitleThe structure of phospho-CDK2/cyclin A in complex with the inhibitor 4,5,6,7-tetrabromobenzotriazole (TBS)
Components
  • Cell division protein kinase 2
  • Cyclin A2
KeywordsCELL CYCLE / Kinase inhibitor / CDK2 / TBS
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 / cellular response to leptin stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / 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 / cellular response to leptin stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / cyclin-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cochlea development / 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 / cellular response to platelet-derived growth factor stimulus / 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 / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / cellular response to nitric oxide / Activation of the pre-replicative complex / animal organ regeneration / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / mitotic G1 DNA damage checkpoint signaling / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G1/S transition of mitotic cell cycle / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / cellular senescence / positive regulation of fibroblast proliferation / 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) / peptidyl-serine phosphorylation / regulation of gene expression / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / Ub-specific processing proteases / endosome / chromatin remodeling / protein phosphorylation / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase 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
4,5,6,7-TETRABROMOBENZOTRIAZOLE / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsDe Moliner, E. / Brown, N.R. / Johnson, L.N.
CitationJournal: Eur.J.Biochem. / Year: 2003
Title: Alternative binding modes of an inhibitor to two different kinases
Authors: De Moliner, E. / Brown, N.R. / Johnson, L.N.
History
DepositionApr 26, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 21, 2016Group: Structure summary

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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)128,4056
Polymers127,5364
Non-polymers8692
Water4,360242
1
A: Cell division protein kinase 2
B: Cyclin A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2033
Polymers63,7682
Non-polymers4351
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3780 Å2
ΔGint-14 kcal/mol
Surface area22980 Å2
MethodPISA
2
C: Cell division protein kinase 2
D: Cyclin A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2033
Polymers63,7682
Non-polymers4351
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3840 Å2
ΔGint-15 kcal/mol
Surface area23430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.536, 133.947, 148.424
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 34143.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2 / Plasmid: PGex 3c / Production host: Escherichia coli (E. coli) / Strain (production host): B834 (DE3) pLysS
References: UniProt: P24941, Transferases; Transferring phosphorus-containing groups; Phosphotransferases with an alcohol group as acceptor
#2: Protein Cyclin A2 / Cyclin A


Mass: 29624.297 Da / Num. of mol.: 2 / Fragment: residues 175-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2 OR CCNA OR CCN1 / Plasmid: pET21d / Production host: Escherichia coli (E. coli) / Strain (production host): B834 (DE3) pLysS / References: UniProt: P20248
#3: Chemical ChemComp-TBS / 4,5,6,7-TETRABROMOBENZOTRIAZOLE / TETRABROMO-2-BENZOTRIAZOLE


Mass: 434.708 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6HBr4N3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 2.86 Å3/Da / Density % sol: 57.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 10 mg/ml pCDK2/cyclin A, 0.5 mM TBS, 1.25 M Ammonium Sulphate, 0.85 M KCl, HEPES 100mM, pH 7, VAPOR DIFFUSION, SITTING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 277 K / pH: 7.4 / Method: vapor diffusion, sitting drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
110 mMHEPES1droppH7.4
2150 mM1dropNaCl
32 mMEDTA1drop
40.01 %azide1drop
50.01 %(v/v)MTG1drop
610 mg/mlprotein1drop
71.25 Mammonium sulfate1reservoir
80.85 M1reservoirKCl
9100 mMHEPES1reservoirpH7.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.934 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 29, 2001
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.22→46.97 Å / Num. all: 73111 / Num. obs: 72014 / % possible obs: 98.5 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.8 % / Biso Wilson estimate: 30.8 Å2 / Rmerge(I) obs: 0.074 / Rsym value: 0.054 / Net I/σ(I): 10.9
Reflection shellResolution: 2.22→2.3 Å / Redundancy: 2.22 % / Rmerge(I) obs: 0.334 / Mean I/σ(I) obs: 3.2 / Num. unique all: 6238 / Rsym value: 0.232 / % possible all: 98.6
Reflection
*PLUS
Rmerge(I) obs: 0.05
Reflection shell
*PLUS
% possible obs: 98.5 % / Redundancy: 2.2 % / Num. unique obs: 6225 / Rmerge(I) obs: 0.232

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
CNSrefinement
CCP4(SCALA)data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.22→46.97 Å / Rfactor Rfree error: 0.003 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.257 5557 8.2 %RANDOM
Rwork0.219 ---
all0.229 67955 --
obs0.219 62398 92.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 34.7439 Å2 / ksol: 0.386293 e/Å3
Displacement parametersBiso mean: 38.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.53 Å20 Å20 Å2
2--0.03 Å20 Å2
3---0.5 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.22→46.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8944 0 26 242 9212
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d21.4
X-RAY DIFFRACTIONc_improper_angle_d0.98
X-RAY DIFFRACTIONc_mcbond_it1.371.5
X-RAY DIFFRACTIONc_mcangle_it2.252
X-RAY DIFFRACTIONc_scbond_it2.192
X-RAY DIFFRACTIONc_scangle_it3.22.5
LS refinement shellResolution: 2.22→2.36 Å / Rfactor Rfree error: 0.011 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.294 778 8.3 %
Rwork0.254 8571 -
obs--77.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2TBB.PARAMTBB.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4TPO.PARAM
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg21.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.98

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