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- PDB-9d0w: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4 -

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Basic information

Entry
Database: PDB / ID: 9d0w
TitleCryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4
Components
  • Cyclin-dependent kinase 2
  • DNA damage-binding protein 1
  • G1/S-specific cyclin-E1
  • Protein cereblon
KeywordsCELL CYCLE / kinase / degrader / ternary complex / CDK2
Function / homology
Function and homology information


positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / negative regulation of monoatomic ion transmembrane transport / RHOBTB3 ATPase cycle / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / cyclin-dependent protein serine/threonine kinase regulator activity / UV-damage excision repair / cyclin A1-CDK2 complex ...positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / negative regulation of monoatomic ion transmembrane transport / RHOBTB3 ATPase cycle / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / cyclin-dependent protein serine/threonine kinase regulator activity / UV-damage excision repair / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / limb development / cyclin E1-CDK2 complex / biological process involved in interaction with symbiont / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / regulation of heterochromatin organization / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / regulation of mitotic cell cycle phase transition / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / WD40-repeat domain binding / G1/S-Specific Transcription / regulation of anaphase-promoting complex-dependent catabolic process / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Association of TriC/CCT with target proteins during biosynthesis / Cul4B-RING E3 ubiquitin ligase complex / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / ubiquitin ligase complex scaffold activity / centrosome duplication / negative regulation of reproductive process / negative regulation of developmental process / microtubule organizing center / locomotory exploration behavior / G0 and Early G1 / viral release from host cell / Telomere Extension By Telomerase / Activation of the pre-replicative complex / cullin family protein binding / cyclin-dependent kinase / DNA replication initiation / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / ectopic germ cell programmed cell death / positive regulation of Wnt signaling pathway / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Cyclin E associated events during G1/S transition / positive regulation of G1/S transition of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / positive regulation of viral genome replication / Cyclin A:Cdk2-associated events at S phase entry / negative regulation of protein-containing complex assembly / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / negative regulation of protein localization to chromatin / regulation of mitotic cell cycle / post-translational protein modification / positive regulation of gluconeogenesis / telomere maintenance / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / potassium ion transport / peptidyl-serine phosphorylation / proteasomal protein catabolic process / sperm end piece / nucleotide-excision repair / sperm principal piece / G1/S transition of mitotic cell cycle / positive regulation of protein-containing complex assembly / meiotic cell cycle / regulation of circadian rhythm / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / G2/M transition of mitotic cell cycle / DNA Damage Recognition in GG-NER / CDK-mediated phosphorylation and removal of Cdc6 / cellular senescence / Wnt signaling pathway / Dual Incision in GG-NER / Transcriptional regulation of granulopoiesis / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / SCF(Skp2)-mediated degradation of p27/p21 / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Cyclin, C-terminal domain / CULT domain / CULT domain profile. / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C ...Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Cyclin, C-terminal domain / CULT domain / CULT domain profile. / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / Cyclin, N-terminal / Cyclin, N-terminal domain / : / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / PUA-like superfamily / 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 / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / 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
: / G1/S-specific cyclin-E1 / Cyclin-dependent kinase 2 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 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: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
C: Cyclin-dependent kinase 2
D: G1/S-specific cyclin-E1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)242,7476
Polymers241,8024
Non-polymers9452
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 4 molecules ABCD

#1: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 128139.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 46465.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: 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
#4: Protein G1/S-specific cyclin-E1


Mass: 33140.578 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

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-A1A1I / (3R)-3-(5-{4-[(2-{4-[(8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]-3-methylbenzene-1-sulfonyl}-7-azaspiro[3.5]nonan-7-yl)methyl]piperidin-1-yl}-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidine-2,6-dione


Mass: 880.041 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H54FN9O6S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
4cryoSPARC4.4.1CTF correction
10cryoSPARC4.41initial Euler assignment
11cryoSPARC4.41final Euler assignment
13cryoSPARC4.4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 537511 / Symmetry type: POINT

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