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- PDB-9d0v: Crystal structure of CDK2/CyclinE1 in complex with Cpd 2 -

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Basic information

Entry
Database: PDB / ID: 9d0v
TitleCrystal structure of CDK2/CyclinE1 in complex with Cpd 2
Components
  • Cyclin-dependent kinase 2
  • G1/S-specific cyclin-E1
KeywordsCELL CYCLE / kinase / degrader
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 / cyclin-dependent protein kinase activity ...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 / cyclin-dependent protein kinase activity / G2 Phase / 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 / G1/S-Specific Transcription / 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) / microtubule organizing center / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / DNA replication initiation / 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 / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / 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 / telomere maintenance / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / male germ cell nucleus / positive regulation of DNA replication / meiotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Wnt signaling pathway / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / G2/M transition of mitotic cell cycle / Cyclin D associated events in G1 / kinase activity / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / peptidyl-serine phosphorylation / 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) / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / chromosome, telomeric region / DNA replication / endosome / protein phosphorylation / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / centrosome / 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 / 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
: / DI(HYDROXYETHYL)ETHER / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsKwiatkowski, N. / Liang, T. / Sha, Z. / Collier, P.N. / Yang, A. / Sathappa, M. / Paul, A. / Su, L. / Zheng, X. / Aversa, R. ...Kwiatkowski, N. / Liang, T. / Sha, Z. / Collier, P.N. / Yang, A. / Sathappa, M. / Paul, A. / Su, L. / Zheng, X. / Aversa, R. / Li, K. / Mehovic, R. / Breitkopf, S.B. / Chen, D. / Howarth, C.L. / Yuan, K. / Jo, H. / Growney, J.D. / Weiss, M. / Williams, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Cell Chem Biol / Year: 2025
Title: CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers.
Authors: Nicholas Kwiatkowski / Tong Liang / Zhe Sha / Philip N Collier / Annan Yang / Murugappan Sathappa / Atanu Paul / Lijing Su / Xiaozhang Zheng / Robert Aversa / Kunhua Li / Revonda Mehovic / ...Authors: Nicholas Kwiatkowski / Tong Liang / Zhe Sha / Philip N Collier / Annan Yang / Murugappan Sathappa / Atanu Paul / Lijing Su / Xiaozhang Zheng / Robert Aversa / Kunhua Li / Revonda Mehovic / Christina Kolodzy / Susanne B Breitkopf / Dapeng Chen / Charles L Howarth / Karen Yuan / Hakryul Jo / Joseph D Growney / Matthew Weiss / Juliet Williams /
Abstract: CCNE1 amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with ...CCNE1 amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with high selectivity for CDK2 over CDK1 that also unexpectedly led to cyclin E1 degradation and potent and complete suppression of RB phosphorylation at concentrations with low CDK2 occupancy and negligible CDK1 degradation. Co-depletion of CDK2 and cyclin E1 also resensitized palbociclib-adapted breast cancer cells to cell cycle blockade. Overall, the improved potency and selectivity of the degrader for CDK2 over small-molecule inhibitors drives antiproliferative activity with greater specificity for CCNE1 cancer cells and RB dependency. Using an orally administered degrader, we demonstrate deep and sustained RB pathway suppression, which is needed to induce stasis in CCNE1 tumors. These results highlight the potential of this modality to target CDK2 potently and selectivity in this biomarker-defined patient population with high unmet need.
History
DepositionAug 7, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)68,29310
Polymers67,2772
Non-polymers1,0168
Water3,117173
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4890 Å2
ΔGint-9 kcal/mol
Surface area23760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.390, 76.390, 257.960
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein , 2 types, 2 molecules AB

#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 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein G1/S-specific cyclin-E1


Mass: 33220.559 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNE1, CCNE / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24864

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Non-polymers , 5 types, 181 molecules

#3: Chemical ChemComp-A1A1H / 6-chloro-8-cyclopentyl-2-[4-(ethanesulfonyl)-2-methylanilino]pyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 446.950 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23ClN4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 173 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.24 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M Bis-Tris pH 6.5, 3.0 M Sodium Chloride, 25% glycerol.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→24.89 Å / Num. obs: 29768 / % possible obs: 100 % / Redundancy: 19.8 % / Rmerge(I) obs: 0.03 / Net I/σ(I): 21.1
Reflection shellResolution: 2.54→2.65 Å / Rmerge(I) obs: 0.132 / Num. unique obs: 2513

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.54→24.89 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 21.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.231 1518 5.1 %
Rwork0.1905 --
obs0.1925 29768 100 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.54→24.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4612 0 67 173 4852
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013
X-RAY DIFFRACTIONf_angle_d1.572
X-RAY DIFFRACTIONf_dihedral_angle_d9.548649
X-RAY DIFFRACTIONf_chiral_restr0.083729
X-RAY DIFFRACTIONf_plane_restr0.012822
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.54-2.620.30071460.24442513X-RAY DIFFRACTION100
2.62-2.720.30011230.22592512X-RAY DIFFRACTION100
2.72-2.820.25591360.2172529X-RAY DIFFRACTION100
2.82-2.950.24341680.21932496X-RAY DIFFRACTION100
2.95-3.110.31151220.23052527X-RAY DIFFRACTION100
3.11-3.30.26951600.20832538X-RAY DIFFRACTION100
3.3-3.560.24061310.19442545X-RAY DIFFRACTION100
3.56-3.910.24341240.17932581X-RAY DIFFRACTION100
3.91-4.480.17361460.15682597X-RAY DIFFRACTION100
4.48-5.630.19581150.17142637X-RAY DIFFRACTION100
5.63-24.890.21471470.18862775X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -34.0862 Å / Origin y: 20.5009 Å / Origin z: 30.0272 Å
111213212223313233
T0.2585 Å20.015 Å20.0474 Å2-0.2613 Å20.0391 Å2--0.2217 Å2
L0.9556 °2-0.4348 °20.2496 °2-1.4125 °2-0.2453 °2--0.3405 °2
S0.0481 Å °0.134 Å °0.1787 Å °-0.3152 Å °-0.1118 Å °-0.0802 Å °0.1505 Å °0.0187 Å °-0.0095 Å °
Refinement TLS groupSelection details: all

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