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- PDB-8vq3: CDK2-CyclinE1 in complex with allosteric inhibitor I-198. -

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Basic information

Entry
Database: PDB / ID: 8vq3
TitleCDK2-CyclinE1 in complex with allosteric inhibitor I-198.
Components
  • Cyclin-dependent kinase 2
  • G1/S-specific cyclin-E1
KeywordsCELL CYCLE/TRANSFERASE/INHIBITOR / kinase / CELL CYCLE-TRANSFERASE-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 / 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-A1AC4 / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsHirschi, M. / Johnson, E. / Zhang, Y. / Liu, Z. / Brodsky, O. / Won, S.J. / Nagata, A. / Petroski, M.D. / Majmudar, J.D. / Niessen, S. ...Hirschi, M. / Johnson, E. / Zhang, Y. / Liu, Z. / Brodsky, O. / Won, S.J. / Nagata, A. / Petroski, M.D. / Majmudar, J.D. / Niessen, S. / VanArsdale, T. / Gilbert, A.M. / Hayward, M.M. / Stewart, A.E. / Nager, A.R. / Melillo, B. / Cravatt, B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA231991 United States
Pfizer United States
CitationJournal: Biorxiv / Year: 2024
Title: Expanding the ligandable proteome by paralog hopping with covalent probes.
Authors: Zhang, Y. / Liu, Z. / Hirschi, M. / Brodsky, O. / Johnson, E. / Won, S.J. / Nagata, A. / Petroski, M.D. / Majmudar, J.D. / Niessen, S. / VanArsdale, T. / Gilbert, A.M. / Hayward, M.M. / ...Authors: Zhang, Y. / Liu, Z. / Hirschi, M. / Brodsky, O. / Johnson, E. / Won, S.J. / Nagata, A. / Petroski, M.D. / Majmudar, J.D. / Niessen, S. / VanArsdale, T. / Gilbert, A.M. / Hayward, M.M. / Stewart, A.E. / Nager, A.R. / Melillo, B. / Cravatt, B.
History
DepositionJan 17, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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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: G1/S-specific cyclin-E1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,7403
Polymers67,1102
Non-polymers6301
Water5,585310
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-16 kcal/mol
Surface area24600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.388, 101.388, 151.613
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein G1/S-specific cyclin-E1


Mass: 33053.500 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-A1AC4 / (8R)-N-[(2S,3R)-3-(cyclohexylmethoxy)-1-(morpholin-4-yl)-1-oxobutan-2-yl]-2-[(1S)-2,2-dimethylcyclopropane-1-carbonyl]-6-(1,3-thiazole-5-carbonyl)-2,6-diazaspiro[3.4]octane-8-carboxamide


Mass: 629.810 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C32H47N5O6S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 57.63 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.21 M sodium citrate tribasic dihydrate, 19.09% PEG3350

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Data collection

DiffractionMean temperature: 98 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 8, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.84→84.28 Å / Num. obs: 68650 / % possible obs: 86.47 % / Redundancy: 26.7 % / Biso Wilson estimate: 38.95 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rsym value: 0.081 / Net I/σ(I): 24.6
Reflection shellResolution: 1.84→1.96 Å / Rmerge(I) obs: 4.49 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1043 / CC1/2: 0.649 / Rsym value: 2.325

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.84→45.23 Å / SU ML: 0.1696 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.9357 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2169 3015 5.08 %
Rwork0.1993 56367 -
obs0.2002 59382 86.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.2 Å2
Refinement stepCycle: LAST / Resolution: 1.84→45.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4527 0 44 310 4881
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01094689
X-RAY DIFFRACTIONf_angle_d1.33986381
X-RAY DIFFRACTIONf_chiral_restr0.2047721
X-RAY DIFFRACTIONf_plane_restr0.01161362
X-RAY DIFFRACTIONf_dihedral_angle_d22.09611718
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.870.495150.3936140X-RAY DIFFRACTION4.75
1.87-1.90.4163330.367623X-RAY DIFFRACTION21.35
1.9-1.930.3629480.29711016X-RAY DIFFRACTION34.43
1.93-1.970.3033830.27191505X-RAY DIFFRACTION51.42
1.97-2.010.27751410.25572347X-RAY DIFFRACTION80.6
2.01-2.050.27451420.24862906X-RAY DIFFRACTION98.51
2.05-2.090.24361590.23992915X-RAY DIFFRACTION100
2.09-2.140.25381540.22092937X-RAY DIFFRACTION100
2.14-2.190.23131460.22622956X-RAY DIFFRACTION100
2.19-2.250.23311560.22652980X-RAY DIFFRACTION100
2.25-2.320.25691540.21842919X-RAY DIFFRACTION100
2.32-2.40.25771540.21832964X-RAY DIFFRACTION100
2.4-2.480.2241410.22462987X-RAY DIFFRACTION100
2.48-2.580.25751640.22972949X-RAY DIFFRACTION100
2.58-2.70.23981640.22572952X-RAY DIFFRACTION100
2.7-2.840.24421560.22652973X-RAY DIFFRACTION100
2.84-3.020.22131630.23312976X-RAY DIFFRACTION99.97
3.02-3.250.23491620.21633002X-RAY DIFFRACTION100
3.25-3.580.21131420.1933026X-RAY DIFFRACTION100
3.58-4.090.18531850.1693020X-RAY DIFFRACTION100
4.09-5.160.16291780.1573056X-RAY DIFFRACTION100
5.16-45.230.22591850.18823218X-RAY DIFFRACTION99.71

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