[English] 日本語
Yorodumi
- PDB-9nyr: Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9nyr
TitleCryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 24
Components
  • Cyclin-dependent kinase 2
  • DNA damage-binding protein 1
  • G1/S-specific cyclin-E1
  • Protein cereblon
KeywordsCELL CYCLE / kinase / degrader / CDK2 / Cyclin E / CRBN
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 / UV-damage excision repair / cyclin-dependent protein serine/threonine kinase regulator activity / biological process involved in interaction with symbiont ...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 / UV-damage excision repair / cyclin-dependent protein serine/threonine kinase regulator activity / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / regulation of heterochromatin organization / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / 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 / Cul4A-RING E3 ubiquitin ligase complex / X chromosome / Cul4-RING E3 ubiquitin ligase complex / G1/S-Specific Transcription / PTK6 Regulates Cell Cycle / Cul4B-RING E3 ubiquitin ligase complex / Association of TriC/CCT with target proteins during biosynthesis / regulation of anaphase-promoting complex-dependent catabolic process / ubiquitin ligase complex scaffold activity / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / negative regulation of reproductive process / negative regulation of developmental process / microtubule organizing center / locomotory exploration behavior / centrosome duplication / G0 and Early G1 / viral release from host cell / cullin family protein binding / DNA replication initiation / Telomere Extension By Telomerase / Activation of the pre-replicative complex / positive regulation of G1/S transition of mitotic cell cycle / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / negative regulation of protein localization to chromatin / positive regulation of Wnt signaling pathway / ectopic germ cell programmed cell death / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cyclin E associated events during G1/S transition / Cajal body / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / Cyclin A:Cdk2-associated events at S phase entry / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / proteasomal protein catabolic process / regulation of G2/M transition of mitotic cell cycle / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / positive regulation of gluconeogenesis / post-translational protein modification / regulation of mitotic cell cycle / telomere maintenance / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / nucleotide-excision repair / positive regulation of protein-containing complex assembly / G1/S transition of mitotic cell cycle / Recognition of DNA damage by PCNA-containing replication complex / peptidyl-serine phosphorylation / regulation of circadian rhythm / potassium ion transport / DNA Damage Recognition in GG-NER / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / CDK-mediated phosphorylation and removal of Cdc6 / G2/M transition of mitotic cell cycle / SCF(Skp2)-mediated degradation of p27/p21 / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Transcriptional regulation of granulopoiesis / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Orc1 removal from chromatin / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Cyclin D associated events in G1
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Lon N-terminal domain profile. / Lon protease, N-terminal domain ...Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / 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 / Cyclin_C / 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 / 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 / WD40-repeat-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / 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: 3.9 Å
AuthorsCollier, P. / Zheng, X. / Ford, M. / Weiss, M. / Aversa, R. / Chen, D. / Li, K. / Growney, J.D. / Yang, A. / Sathappa, M. ...Collier, P. / Zheng, X. / Ford, M. / Weiss, M. / Aversa, R. / Chen, D. / Li, K. / Growney, J.D. / Yang, A. / Sathappa, M. / Breitkopf, S.B. / Enerson, B. / Sawant, R. / Su, L. / Howarth, L. / Liang, T. / Paul, A. / Sharma, K. / Williams, J. / Kwiatkowski, N.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J Med Chem / Year: 2025
Title: Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2.
Authors: Philip N Collier / Xiaozhang Zheng / Melissa Ford / Matthew Weiss / Dapeng Chen / Kunhua Li / Joseph D Growney / Annan Yang / Murugappan Sathappa / Susanne B Breitkopf / Brad Enerson / Tong ...Authors: Philip N Collier / Xiaozhang Zheng / Melissa Ford / Matthew Weiss / Dapeng Chen / Kunhua Li / Joseph D Growney / Annan Yang / Murugappan Sathappa / Susanne B Breitkopf / Brad Enerson / Tong Liang / Atanu Paul / Rupa Sawant / Lijing Su / Robert J Aversa / Charles Howarth / Kirti Sharma / Juliet Williams / Nicholas P Kwiatkowski /
Abstract: Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of cancer, largely because of its potential to overcome the ...Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of cancer, largely because of its potential to overcome the resistance associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors have historically proven challenging due to undesirable safety profiles associated with inhibiting off-target CDK isoforms. Herein, we describe the structure-guided discovery of a series of orally bioavailable and selective degraders of CDK2. Degrader demonstrated improved phenotypic selectivity compared to a clinical CDK2 inhibitor, with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified cancer cells vs nonamplified cohort. The antitumor activity of in mice bearing CCNE1-amplified HCC1569 tumors correlated with sustained >90% degradation of CDK2 and sustained 90% inhibition of Rb phosphorylation.
History
DepositionMar 28, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 4, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)242,7136
Polymers241,8024
Non-polymers9112
Water00
1


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

-
Components

-
Protein , 4 types, 4 molecules DEAB

#1: 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
#2: 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
#3: 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
#4: 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

-
Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-A1B7G / N-{(1R,4S)-4-[(4-{3-chloro-4-[(3R)-2,6-dioxo-1,2,3,6-tetrahydropyridin-3-yl]phenyl}piperazin-1-yl)methyl]cyclohexyl}-4-({4-[(3S)-3-hydroxy-3-methylpiperidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methylbenzene-1-sulfonamide


Mass: 845.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H48ClF3N8O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 24 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Details: 50mM HEPES, pH 7.5, 150mM NaCl, 2mM TCEP, 2 mM FFC8, protein = 13.4 mg/ml
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Chamber temperature: 277 K

-
Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

-
Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
4cryoSPARC4.4.1CTF correction
7PHENIX1.20.1_4487:model fitting
9cryoSPARC4.4.1initial Euler assignment
10cryoSPARC4.4.1final Euler assignment
11cryoSPARC4.4.1classification
12cryoSPARC4.4.13D reconstruction
13PHENIX1.20.1_4487:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 576509
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130033 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 9D0W

9d0w


Accession code: 9D0W / Source name: PDB / Type: experimental model

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more