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- PDB-8vq4: CDK2-CyclinE1 in complex with allosteric inhibitor I-125A. -

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Basic information

Entry
Database: PDB / ID: 8vq4
TitleCDK2-CyclinE1 in complex with allosteric inhibitor I-125A.
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 / 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 ...positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / 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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / G1/S-Specific Transcription / 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 / telomere maintenance in response to DNA damage / microtubule organizing center / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / DNA replication initiation / Activation of the pre-replicative 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 / Cajal body / 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 / 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 / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / telomere maintenance / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Wnt signaling pathway / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / kinase activity / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / regulation of protein localization / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / 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 / cytoplasm / cytosol
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-A1AC5 / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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
Citation
Journal: Nat.Chem.Biol. / Year: 2025
Title: An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes.
Authors: Zhang, Y. / Liu, Z. / Hirschi, M. / Brodsky, O. / Johnson, E. / Won, S.J. / Nagata, A. / Bezwada, D. / Petroski, M.D. / Majmudar, J.D. / Niessen, S. / VanArsdale, T. / Gilbert, A.M. / ...Authors: Zhang, Y. / Liu, Z. / Hirschi, M. / Brodsky, O. / Johnson, E. / Won, S.J. / Nagata, A. / Bezwada, D. / 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.F.
#1: Journal: 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
Revision 1.2Oct 16, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification
Revision 1.3Mar 12, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)67,7713
Polymers67,1102
Non-polymers6611
Water4,071226
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3470 Å2
ΔGint-14 kcal/mol
Surface area24910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.374, 101.374, 151.607
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-A1AC5 / (8R)-6-(1-benzyl-1H-pyrazole-4-carbonyl)-N-[(2S,3R)-3-(2-cyclohexylethoxy)-1-(methylamino)-1-oxobutan-2-yl]-2-[(1S)-2,2-dimethylcyclopropane-1-carbonyl]-2,6-diazaspiro[3.4]octane-8-carboxamide


Mass: 660.846 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C37H52N6O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 226 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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 Å3/Da / Density % sol: 58.94 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 0.21 M sodium citrate tribasic dihydrate, 19.5% PEG3350

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Data collection

DiffractionMean temperature: 98.15 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: 1.842→84.271 Å / Num. obs: 63226 / % possible obs: 79.5 % / Redundancy: 12.4 % / Biso Wilson estimate: 43.15 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.071 / Rsym value: 0.059 / Net I/σ(I): 23.5
Reflection shellResolution: 1.896→2.055 Å / Redundancy: 11.4 % / Rmerge(I) obs: 4.64 / Num. unique obs: 329 / CC1/2: 0.653 / % possible all: 18.8

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7KJS

7kjs


Resolution: 1.9→45.23 Å / SU ML: 0.218 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.6956 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2186 2534 5.04 %
Rwork0.1915 47695 -
obs0.193 50229 79.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.14 Å2
Refinement stepCycle: LAST / Resolution: 1.9→45.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4516 0 48 226 4790
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01384681
X-RAY DIFFRACTIONf_angle_d1.41346363
X-RAY DIFFRACTIONf_chiral_restr0.0773716
X-RAY DIFFRACTIONf_plane_restr0.011354
X-RAY DIFFRACTIONf_dihedral_angle_d21.96021716
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.585640.287485X-RAY DIFFRACTION2.57
1.93-1.970.4122120.3063361X-RAY DIFFRACTION10.84
1.97-2.010.26410.2748874X-RAY DIFFRACTION26.65
2.01-2.060.2393600.25891272X-RAY DIFFRACTION38.32
2.06-2.110.27271070.23761878X-RAY DIFFRACTION57.22
2.11-2.170.2791600.24232924X-RAY DIFFRACTION89.47
2.17-2.230.25651830.24463277X-RAY DIFFRACTION99.63
2.23-2.310.24971900.22633292X-RAY DIFFRACTION100
2.31-2.390.27421840.22233293X-RAY DIFFRACTION100
2.39-2.480.24561590.21783335X-RAY DIFFRACTION100
2.48-2.60.24991780.21853312X-RAY DIFFRACTION100
2.6-2.730.26041850.22113310X-RAY DIFFRACTION100
2.73-2.910.26531590.22843363X-RAY DIFFRACTION100
2.91-3.130.27891810.21433331X-RAY DIFFRACTION99.97
3.13-3.440.24361780.19783364X-RAY DIFFRACTION100
3.44-3.940.18981850.17193389X-RAY DIFFRACTION100
3.94-4.970.16251800.1463420X-RAY DIFFRACTION100
4.97-45.230.20381880.18293615X-RAY DIFFRACTION99.76

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