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- PDB-7kjs: Crystal structure of CDK2/cyclin E in complex with PF-06873600 -

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Basic information

Entry
Database: PDB / ID: 7kjs
TitleCrystal structure of CDK2/cyclin E in complex with PF-06873600
Components
  • Cyclin-dependent kinase 2
  • G1/S-specific cyclin-E1
KeywordsCELL CYCLE / kinase inhibitor
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 / Association of TriC/CCT with target proteins during biosynthesis / regulation of anaphase-promoting complex-dependent catabolic process / 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 / DNA replication initiation / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / cyclin-dependent kinase / Cajal body / 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 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 / response to organic substance / male germ cell nucleus / 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 / Wnt signaling pathway / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / regulation of protein localization / G2/M transition of mitotic cell cycle / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / kinase activity / Processing of DNA double-strand break ends / 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 / regulation of cell cycle / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma ...Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / 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
Similarity search - Domain/homology
Chem-WG1 / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.187 Å
AuthorsMcTigue, M.A. / He, Y. / Ferre, R.A.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer.
Authors: Freeman-Cook, K.D. / Hoffman, R.L. / Behenna, D.C. / Boras, B. / Carelli, J. / Diehl, W. / Ferre, R.A. / He, Y.A. / Hui, A. / Huang, B. / Huser, N. / Jones, R. / Kephart, S.E. / Lapek, J. / ...Authors: Freeman-Cook, K.D. / Hoffman, R.L. / Behenna, D.C. / Boras, B. / Carelli, J. / Diehl, W. / Ferre, R.A. / He, Y.A. / Hui, A. / Huang, B. / Huser, N. / Jones, R. / Kephart, S.E. / Lapek, J. / McTigue, M. / Miller, N. / Murray, B.W. / Nagata, A. / Nguyen, L. / Niessen, S. / Ninkovic, S. / O'Doherty, I. / Ornelas, M.A. / Solowiej, J. / Sutton, S.C. / Tran, K. / Tseng, E. / Visswanathan, R. / Xu, M. / Zehnder, L. / Zhang, Q. / Zhang, C. / Dann, S.
History
DepositionOct 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)68,3763
Polymers67,9052
Non-polymers4721
Water2,594144
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint-17 kcal/mol
Surface area23620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.304, 100.304, 149.982
Angle α, β, γ (deg.)90, 90, 90
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: 34056.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein G1/S-specific cyclin-E1


Mass: 33848.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNE1, CCNE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24864
#3: Chemical ChemComp-WG1 / 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 471.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H27F2N5O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 144 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.9 Å3/Da / Density % sol: 57.58 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES pH 6, .18 M magnesium formate, and 9.0 % (w/v) PEG 20000

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Oct 5, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.187→100.3 Å / Num. obs: 39969 / % possible obs: 99.9 % / Redundancy: 12.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.022 / Rrim(I) all: 0.079 / Rsym value: 0.073 / Net I/σ(I): 17.8
Reflection shellResolution: 2.187→2.3 Å / Redundancy: 12.7 % / Rmerge(I) obs: 1.162 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 5396 / CC1/2: 0.841 / Rpim(I) all: 0.335 / Rrim(I) all: 1.21 / Rsym value: 1.119 / % possible all: 93.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimless0.5.27data scaling
BUSTER2.11.7phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1W98

1w98


Resolution: 2.187→83.38 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.906 / SU R Cruickshank DPI: 0.236 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.238 / SU Rfree Blow DPI: 0.208 / SU Rfree Cruickshank DPI: 0.209
RfactorNum. reflection% reflectionSelection details
Rfree0.2776 1955 -RANDOM
Rwork0.2281 ---
obs0.2305 39893 99 %-
Displacement parametersBiso mean: 61.3 Å2
Baniso -1Baniso -2Baniso -3
1--5.0786 Å20 Å20 Å2
2---5.0786 Å20 Å2
3---10.1572 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.187→83.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4528 0 32 144 4704
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084675HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.956351HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1605SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes767HARMONIC5
X-RAY DIFFRACTIONt_it4675HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion595SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3884SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.91
X-RAY DIFFRACTIONt_other_torsion19.12
LS refinement shellResolution: 2.19→2.2 Å
RfactorNum. reflection% reflection
Rfree0.2806 38 -
Rwork0.2206 --
obs0.2233 798 100 %

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