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- EMDB-46465: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and ... -

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Entry
Database: EMDB / ID: EMD-46465
TitleCryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4 (local mask)
Map data
Sample
  • Complex: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Cyclin-dependent kinase 2
    • Protein or peptide: G1/S-specific cyclin-E1
  • Ligand: ZINC ION
  • Ligand: (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
Keywordskinase / degrader / ternary complex / CELL CYCLE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / Cul4A-RING E3 ubiquitin ligase complex / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex ...negative regulation of monoatomic ion transmembrane transport / positive regulation of mesenchymal stem cell proliferation / homologous chromosome pairing at meiosis / RHOBTB3 ATPase cycle / cyclin-dependent protein serine/threonine kinase regulator activity / Cul4A-RING E3 ubiquitin ligase complex / 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 / locomotory exploration behavior / 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 / positive regulation of Wnt signaling pathway / 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 / negative regulation of protein-containing complex assembly / 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 / positive regulation of protein-containing complex assembly / 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 / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / Ras protein signal transduction / chromosome, telomeric region / DNA replication / endosome / protein ubiquitination / 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
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / 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, C-terminal domain ...Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / 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, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / 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 / 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 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsKwiatkowski N / Liang T / Sha Z / Collier PN / Yang A / Sathappa M / Paul A / Su L / Zheng X / Aversa R ...Kwiatkowski N / Liang T / Sha Z / Collier PN / Yang A / Sathappa M / Paul A / Su L / Zheng X / Aversa R / Li K / Mehovic R / Breitkopf SB / Chen D / Howarth CL / Yuan K / Jo H / Growney JD / Weiss M / Williams J
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateApr 30, 2025-
Current statusApr 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46465.png

Downloads & links

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Map

FileDownload / File: emd_46465.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 352 pix.
= 369.152 Å		1.05 Å/pix.
x 352 pix.
= 369.152 Å		1.05 Å/pix.
x 352 pix.
= 369.152 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04873 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.026820803 - 2.900454
Average (Standard dev.)0.00051717454 (±0.01757224)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 369.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46465_msk_1.map
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Half map: #2

Fileemd_46465_half_map_1.map
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Half map: #1

Fileemd_46465_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4

EntireName: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4
Components
  • Complex: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Cyclin-dependent kinase 2
    • Protein or peptide: G1/S-specific cyclin-E1
  • Ligand: ZINC ION
  • Ligand: (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

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Supramolecule #1: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4

SupramoleculeName: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN and Cpd 4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.465375 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSEAKKPNII NFDTSLPTSH TYLGADMEEF HGRTLHDDDS CQVIPVLPQV MMILIPGQTL PLQLFHPQEV SMVRNLIQKD RTFAVLAYS NVQEREAQFG TTAEIYAYRE EQDFGIEIVK VKAIGRQRFK VLELRTQSDG IQQAKVQILP ECVLPSTMSA V QLESLNKC ...String:
GSEAKKPNII NFDTSLPTSH TYLGADMEEF HGRTLHDDDS CQVIPVLPQV MMILIPGQTL PLQLFHPQEV SMVRNLIQKD RTFAVLAYS NVQEREAQFG TTAEIYAYRE EQDFGIEIVK VKAIGRQRFK VLELRTQSDG IQQAKVQILP ECVLPSTMSA V QLESLNKC QIFPSKPVSR EDQCSYKWWQ KYQKRKFHCA NLTSWPRWLY SLYDAETLMD RIKKQLREWD ENLKDDSLPS NP IDFSYRV AACLPIDDVL RIQLLKIGSA IQRLRCELDI MNKCTSLCCK QCQETEITTK NEIFSLSLCG PMAAYVNPHG YVH ETLTVY KACNLNLIGR PSTEHSWFPG YAWTVAQCKI CASHIGWKFT ATKKDMSPQK FWGLTRSALL PTIPDTEDEI SPDK VILCL

UniProtKB: Protein cereblon

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Macromolecule #2: Cyclin-dependent kinase 2

MacromoleculeName: Cyclin-dependent kinase 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: cyclin-dependent kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.056469 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MENFQKVEKI GEGTYGVVYK ARNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH PNIVKLLDVI HTENKLYLVF EFLHQDLKK FMDASALTGI PLPLIKSYLF QLLQGLAFCH SHRVLHRDLK PQNLLINTEG AIKLADFGLA RAFGVPVRTY (TPO)HEVVTLWY ...String:
MENFQKVEKI GEGTYGVVYK ARNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH PNIVKLLDVI HTENKLYLVF EFLHQDLKK FMDASALTGI PLPLIKSYLF QLLQGLAFCH SHRVLHRDLK PQNLLINTEG AIKLADFGLA RAFGVPVRTY (TPO)HEVVTLWY RAPEILLGCK YYSTAVDIWS LGCIFAEMVT RRALFPGDSE IDQLFRIFRT LGTPDEVVWP GVTSMPD YK PSFPKWARQD FSKVVPPLDE DGRSLLSQML HYDPNKRISA KAALAHPFFQ DVTKPVPHLR L

UniProtKB: Cyclin-dependent kinase 2

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Macromolecule #3: G1/S-specific cyclin-E1

MacromoleculeName: G1/S-specific cyclin-E1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.140578 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SGSIIAPSRG SPLPVLSWAN REEVWKIMLN KEKTYLRDQH FLEQHPLLQP KMRAILLDWL MEVCEVYKLH RETFYLAQDF FDRYMATQE NVVKTLLQLI GISSLFIAAK LEEIYPPKLH QFAYVTDGAC SGDEILTMEL MIMKALKWRL SPLTIVSWLN V YMQVAYLN ...String:
SGSIIAPSRG SPLPVLSWAN REEVWKIMLN KEKTYLRDQH FLEQHPLLQP KMRAILLDWL MEVCEVYKLH RETFYLAQDF FDRYMATQE NVVKTLLQLI GISSLFIAAK LEEIYPPKLH QFAYVTDGAC SGDEILTMEL MIMKALKWRL SPLTIVSWLN V YMQVAYLN DLHEVLLPQY PQQIFIQIAE LLDLCVLDVD CLEFPYGILA ASALYHFSSS ELMQKVSGYQ WCDIENCVKW MV PFAMVIR ETGSSKLKHF RGVADEDAHN IQTHRDSLDL LDKARAKKA

UniProtKB: G1/S-specific cyclin-E1

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: (3R)-3-(5-{4-[(2-{4-[(8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d...

MacromoleculeName: (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- ...Name: (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
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1A1I
Molecular weightTheoretical: 880.041 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 537511
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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