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- EMDB-69485: Cryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11 conse... -

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Entry
Database: EMDB / ID: EMD-69485
TitleCryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11 consensus refinement
Map data
Sample
  • Complex: CDK2 in complex with CRBN/DDB1 and B11
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Cyclin-dependent kinase 2
    • Protein or peptide: DNA damage-binding protein 1
KeywordsCyclin-Dependent Kinase 2 / Cereblon / Molecular glue / Complex / CELL CYCLE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / G2 Phase ...negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / regulation of heterochromatin organization / biological process involved in interaction with symbiont / 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 / regulation of mitotic cytokinesis / X chromosome / regulation of mitotic cell cycle phase transition / PTK6 Regulates Cell Cycle / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / locomotory exploration behavior / regulation of cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / centriole replication / Cul4B-RING E3 ubiquitin ligase complex / telomere maintenance in response to DNA damage / Regulation of APC/C activators between G1/S and early anaphase / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / G0 and Early G1 / regulation of cellular response to stress / limb development / viral release from host cell / Activation of the pre-replicative complex / Telomere Extension By Telomerase / cyclin-dependent protein kinase holoenzyme complex / cyclin-dependent kinase / cullin family protein binding / 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 / positive regulation of Wnt signaling pathway / Cyclin E associated events during G1/S transition / negative regulation of protein-containing complex assembly / regulation of DNA-templated DNA replication initiation / centrosome duplication / Cyclin A:Cdk2-associated events at S phase entry / positive regulation of viral genome replication / positive regulation of gluconeogenesis / Cyclin A/B1/B2 associated events during G2/M transition / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / regulation of embryonic development / cyclin binding / positive regulation of DNA replication / replication fork processing / negative regulation of protein localization to chromatin / regulation of mitotic cell cycle / G1/S transition of mitotic cell cycle / G2/M transition of mitotic cell cycle / proteasomal protein catabolic process / epigenetic regulation of gene expression / positive regulation of protein-containing complex assembly / nucleotide-excision repair / meiotic cell cycle / peptidyl-serine phosphorylation / cellular senescence / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage/Telomere Stress Induced Senescence / regulation of circadian rhythm / Meiotic recombination / cell population proliferation / DNA Damage Recognition in GG-NER / CDK-mediated phosphorylation and removal of Cdc6 / Dual Incision in GG-NER / SCF(Skp2)-mediated degradation of p27/p21 / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Transcriptional regulation of granulopoiesis / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / Orc1 removal from chromatin / positive regulation of protein catabolic process / cellular response to UV / Cyclin D associated events in G1 / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of TP53 Degradation
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) / : ...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) / : / 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 / : / 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
Cyclin-dependent kinase 2 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.69 Å
AuthorsLi XZ / Jiang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Med Chem / Year: 2026
Title: Selective CDK2 Degradation via Noncanonical Recruitment.
Authors: Yuanyuan Pei / Weiye Lin / Xinzhu Li / Yuhang Meng / Yuling Yin / Benxun Pan / Lixin Zhou / Linhui Cao / Yong Cang / Yi Jiang / Wenchao Lu / Zhanchao Meng /
Abstract: Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with amplification. However, selective inhibition of CDK2 remains challenging ...Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with amplification. However, selective inhibition of CDK2 remains challenging owing to the high structural homology among CDKs. In this study, we identify and as cereblon (CRBN)-based molecular glue degraders that selectively degrade CDK2. Ternary complex structures reveal a noncanonical recruitment mode centered on CDK2 Glu57, which bypasses the canonical G-loop/β-hairpin and kinase glycine-rich loop interactions and is stabilized by an extended CRBN-CDK2 interface. Mechanistically, these degraders inhibit retinoblastoma (Rb) phosphorylation and induce G1/S-phase arrest, suppressing CDK2-dependent cell proliferation. further exhibits improved pharmacokinetics, measurable oral bioavailability, and target engagement, achieving intratumoral CDK2 degradation following intraperitoneal administration. Collectively, this study provides a structural blueprint for designing selective kinase degraders and establishes B12 as a chemically tractable probe for targeting CDK2-driven malignancies.
History
DepositionMar 2, 2026-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_69485.png

Downloads & links

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Map

FileDownload / File: emd_69485.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 296.64 Å		0.82 Å/pix.
x 360 pix.
= 296.64 Å		0.82 Å/pix.
x 360 pix.
= 296.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
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Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.30717242 - 0.6588678
Average (Standard dev.)-0.00030514013 (±0.01356788)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 296.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_69485_additional_1.map
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Additional map: #2

Fileemd_69485_additional_2.map
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Half map: #1

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Half map: #2

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Sample components

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Entire : CDK2 in complex with CRBN/DDB1 and B11

EntireName: CDK2 in complex with CRBN/DDB1 and B11
Components
  • Complex: CDK2 in complex with CRBN/DDB1 and B11
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Cyclin-dependent kinase 2
    • Protein or peptide: DNA damage-binding protein 1

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Supramolecule #1: CDK2 in complex with CRBN/DDB1 and B11

SupramoleculeName: CDK2 in complex with CRBN/DDB1 and B11 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH GSDYKDDDDV DYDIPTTENL YFQGAMGSEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQVI PVLPQVMMIL IPGQTLPLQL FHPQEVSMVR NLIQKDRTFA VLAYSNVQER EAQFGTTAEI YAYREEQDFG IEIVKVKAIG RQRFKVLELR ...String:
MSYYHHHHHH GSDYKDDDDV DYDIPTTENL YFQGAMGSEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQVI PVLPQVMMIL IPGQTLPLQL FHPQEVSMVR NLIQKDRTFA VLAYSNVQER EAQFGTTAEI YAYREEQDFG IEIVKVKAIG RQRFKVLELR TQSDGIQQAK VQILPECVLP STMSAVQLES LNKCQIFPSK PVSREDQCSY KWWQKYQKRK FHCANLTSWP RWLYSLYDAE TLMDRIKKQL REWDENLKDD SLPSNPIDFS YRVAACLPID DVLRIQLLKI GSAIQRLRCE LDIMNKCTSL CCKQCQETEI TTKNEIFSLS LCGPMAAYVN PHGYVHETLT VYKACNLNLI GRPSTEHSWF PGYAWTVAQC KICASHIGWK FTATKKDMSP QKFWGLTRSA LLPTIPDTED EISPDKVILC LGSSGGGGSG GGSSGGGGSG GGGSSGVSGW RLFKKIS

UniProtKB: Protein cereblon

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Macromolecule #2: Cyclin-dependent kinase 2

MacromoleculeName: Cyclin-dependent kinase 2 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIGSPTTE NLYFQGAATM VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHVI IPYEGLSADQ MAQIEEVFKV VYPVDDHHFK VILPYGTLVI DGVTPNMLNY FGRPYEGIAV FDGKKITVTG TLWNGNKIID ...String:
MSYYHHHHHH DYDIGSPTTE NLYFQGAATM VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHVI IPYEGLSADQ MAQIEEVFKV VYPVDDHHFK VILPYGTLVI DGVTPNMLNY FGRPYEGIAV FDGKKITVTG TLWNGNKIID ERLITPDGSM LFRVTINSGS SGGGGSGGGG SSMENFQKVE KIGEGTYGVV YKARNKLTGE VVALKKIRLD TETEGVPSTA IREISLLKEL NHPNIVKLLD VIHTENKLYL VFEFLHQDLK KFMDASALTG IPLPLIKSYL FQLLQGLAFC HSHRVLHRDL KPQNLLINTE GAIKLADFGL ARAFGVPVRT YTHEVVTLWY RAPEILLGCK YYSTAVDIWS LGCIFAEMVT RRALFPGDSE IDQLFRIFRT LGTPDEVVWP GVTSMPDYKP SFPKWARQDF SKVVPPLDED GRSLLSQMLH YDPNKRISAK AALAHPFFQD VTKPVPHLRL ENLYFQGGGS GGSSVIKPEM KIKLRMEGAV NGHKFVIEGE GIGKPYEGTQ TLDLTVEEGA PLPFSYDILT PAFQYGNRAF TKYPEDIPDY FKQAFPEGYS WERSMTYEDQ GICIATSDIT MEGDCFFYEI RFDGTNFPPN GPVMQKKTLK WEPSTEKMYV EDGVLKGDVE MALLLEGGGH YRCDFKTTYK AKKDVRLPDA HEVDHRIEIL SHDKDYNKVR LYEHAEARY

UniProtKB: Cyclin-dependent kinase 2

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Macromolecule #3: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL YGCQAPTICF VYQDPQGRHV KTYEVSLREK EFNKGPWKQE NVEAEASMVI AVPEPFGGAI IIGQESITYH NGDKYLAIAP PIIKQSTIVC HNRVDPNGSR YLLGDMEGRL FMLLLEKEEQ MDGTVTLKDL RVELLGETSI AECLTYLDNG VVFVGSRLGD SQLVKLNVDS NEQGSYVVAM ETFTNLGPIV DMCVVDLERQ GQGQLVTCSG AFKEGSLRII RNGIGGNGNS GEIQKLHIRT VPLYESPRKI CYQEVSQCFG VLSSRIEVQD TSGGTTALRP SASTQALSSS VSSSKLFSSS TAPHETSFGE EVEVHNLLII DQHTFEVLHA HQFLQNEYAL SLVSCKLGKD PNTYFIVGTA MVYPEEAEPK QGRIVVFQYS DGKLQTVAEK EVKGAVYSMV EFNGKLLASI NSTVRLYEWT TEKELRTECN HYNNIMALYL KTKGDFILVG DLMRSVLLLA YKPMEGNFEE IARDFNPNWM SAVEILDDDN FLGAENAFNL FVCQKDSAAT TDEERQHLQE VGLFHLGEFV NVFCHGSLVM QNLGETSTPT QGSVLFGTVN GMIGLVTSLS ESWYNLLLDM QNRLNKVIKS VGKIEHSFWR SFHTERKTEP ATGFIDGDLI ESFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1

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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

Concentration14 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.69 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot / Number images used: 498215
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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