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- PDB-10dw: Structure of CRBN/DDB1dB-KAT2A-Compound4 ternary complex -

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Basic information

Entry
Database: PDB / ID: 10dw
TitleStructure of CRBN/DDB1dB-KAT2A-Compound4 ternary complex
Components
  • DNA damage-binding protein 1
  • Histone acetyltransferase KAT2A
  • Protein cereblon
KeywordsTRANSFERASE / CRBN / molecular glue / CRBN-MG / KAT2A
Function / homology
Function and homology information


histone H1-4K34 acetyltransferase activity / negative regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / histone succinyltransferase activity / peptidyl-lysine glutarylation / histone glutaryltransferase activity / regulation of cartilage development / regulation of bone development / regulation of regulatory T cell differentiation / histone H4K12 acetyltransferase activity / histone H3K9 acetyltransferase activity ...histone H1-4K34 acetyltransferase activity / negative regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / histone succinyltransferase activity / peptidyl-lysine glutarylation / histone glutaryltransferase activity / regulation of cartilage development / regulation of bone development / regulation of regulatory T cell differentiation / histone H4K12 acetyltransferase activity / histone H3K9 acetyltransferase activity / negative regulation of centriole replication / positive regulation of cell projection organization / transcription factor TFTC complex / negative regulation of monoatomic ion transmembrane transport / positive regulation of cardiac muscle cell differentiation / internal peptidyl-lysine acetylation / histone H3 acetyltransferase activity / regulation of T cell activation / histone H3K18 acetyltransferase activity / SAGA complex / ATAC complex / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / positive regulation by virus of viral protein levels in host cell / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Cardiogenesis / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / NOTCH3 Intracellular Domain Regulates Transcription / regulation of tubulin deacetylation / UV-damage excision repair / Notch-HLH transcription pathway / biological process involved in interaction with symbiont / Formation of paraxial mesoderm / acetyltransferase activity / regulation of mitotic cytokinesis / histone acetyltransferase activity / regulation of mitotic cell cycle phase transition / Formation of WDR5-containing histone-modifying complexes / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding / locomotory exploration behavior / regulation of cell cycle phase transition / regulation of RNA splicing / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / intracellular distribution of mitochondria / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / RNA Polymerase I Transcription Initiation / regulation of cellular response to stress / histone acetyltransferase complex / limb development / viral release from host cell / negative regulation of gluconeogenesis / regulation of cell division / cullin family protein binding / protein-lysine-acetyltransferase activity / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / regulation of DNA-templated DNA replication initiation / long-term memory / histone acetyltransferase / positive regulation of viral genome replication / positive regulation of gluconeogenesis / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / regulation of DNA repair / regulation of embryonic development / replication fork processing / positive regulation of cytokine production / cellular response to tumor necrosis factor / proteasomal protein catabolic process / regulation of protein stability / cellular response to nerve growth factor stimulus / epigenetic regulation of gene expression / positive regulation of protein-containing complex assembly / regulation of synaptic plasticity / nucleotide-excision repair / response to nutrient levels / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / mitotic spindle / B-WICH complex positively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / regulation of circadian rhythm / Pre-NOTCH Transcription and Translation / cell population proliferation / DNA Damage Recognition in GG-NER / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / heart development / Formation of Incision Complex in GG-NER / positive regulation of protein catabolic process
Similarity search - Function
PCAF, N-terminal / Histone acetyltransferase GCN5/PCAF / PCAF (P300/CBP-associated factor) N-terminal domain / Histone acetyltransferase GCN5 / 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 ...PCAF, N-terminal / Histone acetyltransferase GCN5/PCAF / PCAF (P300/CBP-associated factor) N-terminal domain / Histone acetyltransferase GCN5 / 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 / Acetyltransferase (GNAT) family / PUA-like superfamily / Gcn5-related N-acetyltransferase (GNAT) domain profile. / GNAT domain / Acyl-CoA N-acyltransferase / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / DNA damage-binding protein 1 / Histone acetyltransferase KAT2A / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsOjeda, S. / Fischer, E.S.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)P01CA066996 United States
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)R01CA262188 United States
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)R01CA214608 United States
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)R01CA218278 United States
CitationJournal: Science / Year: 2026
Title: Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
Authors: Samuel Ojeda / Meng Wang / Kheewoong Baek / Wallace Bourgeois / Alba Sommerschield / Hong Yue / Rebecca J Metivier / Panos Karagiannis / Talya S Levitz / Yuan Xiong / Katherine A Donovan / ...Authors: Samuel Ojeda / Meng Wang / Kheewoong Baek / Wallace Bourgeois / Alba Sommerschield / Hong Yue / Rebecca J Metivier / Panos Karagiannis / Talya S Levitz / Yuan Xiong / Katherine A Donovan / Scott A Armstrong / Eric S Fischer /
Abstract: Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins ...Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)-based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.
History
DepositionJan 14, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone acetyltransferase KAT2A
C: Protein cereblon
B: DNA damage-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,7167
Polymers189,9193
Non-polymers7974
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Histone acetyltransferase KAT2A / General control of amino acid synthesis protein 5-like 2 / Histone acetyltransferase GCN5 / hGCN5 / ...General control of amino acid synthesis protein 5-like 2 / Histone acetyltransferase GCN5 / hGCN5 / Histone glutaryltransferase KAT2A / Histone succinyltransferase KAT2A / Lysine acetyltransferase 2A / STAF97


Mass: 38581.309 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal Strep-TEV tagged KAT2A-NTD / Source: (gene. exp.) Homo sapiens (human) / Gene: KAT2A, GCN5, GCN5L2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q92830, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Protein Protein cereblon


Mass: 55144.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N terminal Flag-Spy tagged CRBN / Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SW2
#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: 96193.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N terminal His tagged DDB1dB,N terminal His tagged DDB1dB
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-A1C5C / (3S)-3-[4-({6-(3-tert-butyl-2-oxoimidazolidin-1-yl)-1-[(2S)-oxan-2-yl]-1H-imidazo[4,5-c]pyridin-4-yl}amino)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione


Mass: 600.668 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H36N8O5 / 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

Component
IDNameTypeEntity IDParent-IDSource
1Compound 4 induced DDB1dB/CRBN, KAT2A-NTD ternary complexCOMPLEX#1, #3, #20RECOMBINANT
2DDB1dB/CRBNCOMPLEX#3, #21RECOMBINANT
3KAT2A N-terminal domainCOMPLEX#11RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Trichoplusia ni (cabbage looper)7111
32Trichoplusia ni (cabbage looper)7111
43Escherichia coli (E. coli)562
Buffer solutionpH: 7.4 / Details: 30 mM HEPES/NaOH pH7.4, 150 mM NaCl.
Buffer component
IDConc.NameFormulaBuffer-ID
130 mMHEPESC8H18N2O4S1
2150 mMSodium chlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R0.6/1
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283 K
Details: Grids were vitrified using a Leica EM GP plunge freezer operated at 90% humidity and 10C. Grids were first pre-incubated with 4uL of 10uM CRBN-agnostic IKZF1_140-196_Q146A,G151N for 1 minute ...Details: Grids were vitrified using a Leica EM GP plunge freezer operated at 90% humidity and 10C. Grids were first pre-incubated with 4uL of 10uM CRBN-agnostic IKZF1_140-196_Q146A,G151N for 1 minute and then back-blotted for 4s. Afterwards, 4uL of mixture was applied to the grids, followed by blotting for 4s and plunging into liquid ethane at -181 C.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS / Details: The grid was imaged at a 30-degree tilt
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 55.8 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9381 / Details: The grid was imaged at a 30-degree tilt

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.21.2_5419model refinement
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 613163 / Symmetry type: POINT
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211247
ELECTRON MICROSCOPYf_angle_d0.50115213
ELECTRON MICROSCOPYf_dihedral_angle_d4.7741518
ELECTRON MICROSCOPYf_chiral_restr0.0431711
ELECTRON MICROSCOPYf_plane_restr0.0041949

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