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- PDB-5l2w: The X-ray co-crystal structure of human CDK2/CyclinE and Dinaciclib. -

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Basic information

Entry
Database: PDB / ID: 5l2w
TitleThe X-ray co-crystal structure of human CDK2/CyclinE and Dinaciclib.
Components
  • Cyclin-dependent kinase 2
  • G1/S-specific cyclin-E1
KeywordsTransferase/Cell Cycle/Inhibitor / cyclin-dependent kinase / kinase inhibitor / kinase selectivity / Transferase-Cell Cycle-Inhibitor complex
Function / homology
Function and homology information


positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / G1/S-Specific Transcription / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation ...positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / G1/S-Specific Transcription / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / 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 / Association of TriC/CCT with target proteins during biosynthesis / 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 / DNA replication initiation / cellular response to nitric oxide / cyclin-dependent protein kinase holoenzyme complex / positive regulation of G1/S transition of mitotic cell cycle / cyclin-dependent kinase / 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 / Cajal body / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / telomere maintenance / cyclin binding / post-translational protein modification / : / meiotic cell cycle / positive regulation of DNA replication / male germ cell nucleus / 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 / Wnt signaling pathway / Orc1 removal from chromatin / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / regulation of protein localization / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / kinase activity / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / DNA replication / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / endosome / chromatin remodeling / protein domain specific binding / cell division / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA-templated transcription / centrosome / 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 / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
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, 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-1QK / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsChen, P. / Ferre, R.A. / Deihl, W. / Yu, X. / He, Y.-A.
CitationJournal: Mol.Cancer Ther. / Year: 2016
Title: Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance.
Authors: Chen, P. / Lee, N.V. / Hu, W. / Xu, M. / Ferre, R.A. / Lam, H. / Bergqvist, S. / Solowiej, J. / Diehl, W. / He, Y.A. / Yu, X. / Nagata, A. / VanArsdale, T. / Murray, B.W.
History
DepositionAug 2, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Oct 4, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cyclin-dependent kinase 2
B: G1/S-specific cyclin-E1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3234
Polymers69,8342
Non-polymers4902
Water1,35175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3850 Å2
ΔGint-19 kcal/mol
Surface area23440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.307, 100.307, 151.857
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 34143.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein G1/S-specific cyclin-E1


Mass: 35690.262 Da / Num. of mol.: 1 / Fragment: UNP residues 81-363
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNE1, CCNE / Production host: Escherichia coli (E. coli) / References: UniProt: P24864
#3: Chemical ChemComp-1QK / 3-[({3-ethyl-5-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)methyl]-1-hydroxypyridinium / DINACICLIB


Mass: 397.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 2.73 Å3/Da / Density % sol: 55.03 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop / Details: PEG20K, 180mM Mg(HCO2)2, 0.1M MES pH 6.0

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Data collection

DiffractionMean temperature: 98.15 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→45 Å / Num. obs: 19770 / % possible obs: 99.9 % / Redundancy: 12.76 % / Biso Wilson estimate: 100.25 Å2 / Net I/σ(I): 22.9

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
autoXDSdata processing
BUSTERphasing
Aimlessdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1W98

1w98


Resolution: 2.8→45 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.9244 / SU R Cruickshank DPI: 1.334 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 2.166 / SU Rfree Blow DPI: 0.335 / SU Rfree Cruickshank DPI: 0.337
RfactorNum. reflection% reflectionSelection details
Rfree0.2463 962 4.87 %RANDOM
Rwork0.1995 ---
obs0.2019 19741 99.99 %-
Displacement parametersBiso mean: 84.34 Å2
Baniso -1Baniso -2Baniso -3
1--6.1078 Å20 Å20 Å2
2---6.1078 Å20 Å2
3---12.2156 Å2
Refine analyzeLuzzati coordinate error obs: 0.378 Å
Refinement stepCycle: 1 / Resolution: 2.8→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4608 0 35 75 4718
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014774HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.156482HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1661SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes109HARMONIC2
X-RAY DIFFRACTIONt_gen_planes693HARMONIC5
X-RAY DIFFRACTIONt_it4774HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion21.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion604SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5661SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.95 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3483 129 4.56 %
Rwork0.245 2699 -
all0.2501 2828 -
obs--99.99 %

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