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- EMDB-69221: Cryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11 -

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Entry
Database: EMDB / ID: EMD-69221
TitleCryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11
Map data
Sample
  • Complex: CDK2 in complex with CRBN/DDB1 and B11
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: spiro[3.3]heptan-2-ylmethyl ~{N}-[[3-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]-8-chloranyl-6-fluoranyl-4-oxidanylidene-quinazolin-7-yl]methyl]carbamate
KeywordsCyclin-Dependent Kinase 2 / Cereblon / Molecular glue / Complex / CELL CYCLE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / 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 / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes ...negative regulation of monoatomic ion transmembrane transport / 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 / 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 / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / locomotory exploration behavior / Cul4A-RING E3 ubiquitin ligase complex / centriole replication / telomere maintenance in response to DNA damage / Regulation of APC/C activators between G1/S and early anaphase / G0 and Early G1 / limb development / Activation of the pre-replicative complex / Telomere Extension By Telomerase / cyclin-dependent protein kinase holoenzyme complex / 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 / positive regulation of Wnt signaling pathway / Cyclin E associated events during G1/S transition / negative regulation of protein-containing complex assembly / centrosome duplication / Cyclin A:Cdk2-associated events at S phase entry / 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 / cyclin binding / positive regulation of DNA replication / 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 / positive regulation of protein-containing complex assembly / meiotic cell cycle / peptidyl-serine phosphorylation / cellular senescence / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / Cyclin D associated events in G1 / Regulation of TP53 Degradation / nuclear envelope / transcription regulator complex / Factors involved in megakaryocyte development and platelet production / ciliary basal body / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / Regulation of TP53 Activity through Phosphorylation / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / Ras protein signal transduction / transmembrane transporter binding / DNA replication / protein phosphorylation / chromosome, telomeric region / endosome / protein ubiquitination / chromatin remodeling / protein domain specific binding / protein serine kinase activity / cell division / DNA repair / protein serine/threonine kinase activity / centrosome / positive regulation of cell population proliferation / perinuclear region of cytoplasm / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / membrane / metal ion binding / nucleus / cytosol / cytoplasm
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) / PUA-like superfamily ...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) / 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 / 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 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.85 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
DepositionFeb 16, 2026-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_69221.png

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Map

FileDownload / File: emd_69221.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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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

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Voxel sizeX=Y=Z: 0.824 Å
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Contour LevelBy AUTHOR: 0.122
Minimum - Maximum-0.25313783 - 0.84744674
Average (Standard dev.)0.0013693046 (±0.013918459)
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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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: Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: spiro[3.3]heptan-2-ylmethyl ~{N}-[[3-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]-8-chloranyl-6-fluoranyl-4-oxidanylidene-quinazolin-7-yl]methyl]carbamate

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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: #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: 53.781996 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH GSDYKDDDDV DYDIPTTENL YFQGAMGSEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQVI PVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI G RQRFKVLE ...String:
MSYYHHHHHH GSDYKDDDDV DYDIPTTENL YFQGAMGSEA KKPNIINFDT SLPTSHTYLG ADMEEFHGRT LHDDDSCQVI PVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI G RQRFKVLE LRTQSDGIQQ AKVQILPECV LPSTMSAVQL ESLNKCQIFP SKPVSREDQC SYKWWQKYQK RKFHCANLTS WP RWLYSLY DAETLMDRIK KQLREWDENL KDDSLPSNPI DFSYRVAACL PIDDVLRIQL LKIGSAIQRL RCELDIMNKC TSL CCKQCQ ETEITTKNEI FSLSLCGPMA AYVNPHGYVH ETLTVYKACN LNLIGRPSTE HSWFPGYAWT VAQCKICASH IGWK FTATK KDMSPQKFWG LTRSALLPTI PDTEDEISPD KVILCLGSSG GGGSGGGSSG GGGSGGGGSS GVSGWRLFKK IS

UniProtKB: Protein cereblon

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Macromolecule #2: Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dep...

MacromoleculeName: Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: cyclin-dependent kinase
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 82.203477 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIGSPTTE NLYFQGAATM VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHV IIPYEGLSAD QMAQIEEVFK VVYPVDDHHF KVILPYGTLV IDGVTPNMLN YFGRPYEGIA VFDGKKITVT G TLWNGNKI ...String:
MSYYHHHHHH DYDIGSPTTE NLYFQGAATM VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHV IIPYEGLSAD QMAQIEEVFK VVYPVDDHHF KVILPYGTLV IDGVTPNMLN YFGRPYEGIA VFDGKKITVT G TLWNGNKI IDERLITPDG SMLFRVTINS GSSGGGGSGG GGSSMENFQK VEKIGEGTYG VVYKARNKLT GEVVALKKIR LD TETEGVP STAIREISLL KELNHPNIVK LLDVIHTENK LYLVFEFLHQ DLKKFMDASA LTGIPLPLIK SYLFQLLQGL AFC HSHRVL HRDLKPQNLL INTEGAIKLA DFGLARAFGV PVRTYTHEVV TLWYRAPEIL LGCKYYSTAV DIWSLGCIFA EMVT RRALF PGDSEIDQLF RIFRTLGTPD EVVWPGVTSM PDYKPSFPKW ARQDFSKVVP PLDEDGRSLL SQMLHYDPNK RISAK AALA HPFFQDVTKP VPHLRLENLY FQGGGSGGSS VIKPEMKIKL RMEGAVNGHK FVIEGEGIGK PYEGTQTLDL TVEEGA PLP FSYDILTPAF QYGNRAFTKY PEDIPDYFKQ AFPEGYSWER SMTYEDQGIC IATSDITMEG DCFFYEIRFD GTNFPPN GP VMQKKTLKWE PSTEKMYVED GVLKGDVEMA LLLEGGGHYR CDFKTTYKAK KDVRLPDAHE VDHRIEILSH DKDYNKVR L YEHAEARY

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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK FLYGCQAPTI CFVYQDPQGR HVKTYEVSLR EKEFNKGPWK QENVEAEASM VIAVPEPFGG AIIIGQESIT YH NGDKYLA IAPPIIKQST IVCHNRVDPN GSRYLLGDME GRLFMLLLEK EEQMDGTVTL KDLRVELLGE TSIAECLTYL DNG VVFVGS RLGDSQLVKL NVDSNEQGSY VVAMETFTNL GPIVDMCVVD LERQGQGQLV TCSGAFKEGS LRIIRNGIGG NGNS GEIQK LHIRTVPLYE SPRKICYQEV SQCFGVLSSR IEVQDTSGGT TALRPSASTQ ALSSSVSSSK LFSSSTAPHE TSFGE EVEV HNLLIIDQHT FEVLHAHQFL QNEYALSLVS CKLGKDPNTY FIVGTAMVYP EEAEPKQGRI VVFQYSDGKL QTVAEK EVK GAVYSMVEFN GKLLASINST VRLYEWTTEK ELRTECNHYN NIMALYLKTK GDFILVGDLM RSVLLLAYKP MEGNFEE IA RDFNPNWMSA VEILDDDNFL GAENAFNLFV CQKDSAATTD EERQHLQEVG LFHLGEFVNV FCHGSLVMQN LGETSTPT Q GSVLFGTVNG MIGLVTSLSE SWYNLLLDMQ NRLNKVIKSV GKIEHSFWRS FHTERKTEPA TGFIDGDLIE SFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

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Macromolecule #4: spiro[3.3]heptan-2-ylmethyl ~{N}-[[3-[(3~{R})-2,6-bis(oxidanylide...

MacromoleculeName: spiro[3.3]heptan-2-ylmethyl ~{N}-[[3-[(3~{R})-2,6-bis(oxidanylidene)piperidin-3-yl]-8-chloranyl-6-fluoranyl-4-oxidanylidene-quinazolin-7-yl]methyl]carbamate
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1E59
Molecular weightTheoretical: 490.912 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

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: 2.85 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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