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- PDB-23sr: Cryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11 -

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Basic information

Entry
Database: PDB / ID: 23sr
TitleCryo-EM structure of CDK2 in complex with CRBN/DDB1 and B11
Components
  • DNA damage-binding protein 1
  • Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein
  • Protein cereblon
KeywordsCELL CYCLE / Cyclin-Dependent Kinase 2 / Cereblon / Molecular glue / Complex
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsLi, X.Z. / Jiang, Y.
Funding support China, 1items
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, 2026Deposition site: PDBJ / Processing site: PDBC
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein cereblon
C: Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein
A: DNA damage-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)229,8234
Polymers229,3333
Non-polymers4911
Water00
1


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

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Components

#1: Protein Protein cereblon


Mass: 53781.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / Variant (production host): WT / References: UniProt: Q96SW2
#2: Protein Oplophorus-luciferin 2-monooxygenase catalytic subunit,Cyclin-dependent kinase 2,GFP-like fluorescent chromoprotein / Cell division protein kinase 2 / p33 protein kinase


Mass: 82203.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others), (gene. exp.) Homo sapiens (human)
Plasmid: pFastBac / Gene: CDK2, CDKN2 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#3: Protein DNA damage-binding protein 1


Mass: 93347.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
#4: Chemical ChemComp-A1E59 / 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


Mass: 490.912 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24ClFN4O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: CDK2 in complex with CRBN/DDB1 and B11 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9 / Plasmid: pFastBac
Buffer solutionpH: 7.4
SpecimenConc.: 14 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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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: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13Coot3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 498215 / Symmetry type: POINT
RefinementHighest resolution: 2.85 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00311914
ELECTRON MICROSCOPYf_angle_d0.51516176
ELECTRON MICROSCOPYf_dihedral_angle_d5.0611615
ELECTRON MICROSCOPYf_chiral_restr0.0431847
ELECTRON MICROSCOPYf_plane_restr0.0042074

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