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- EMDB-47174: Cryo-EM Structure of CRBN:dHTC1:ENL YEATS -

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Basic information

Entry
Database: EMDB / ID: EMD-47174
TitleCryo-EM Structure of CRBN:dHTC1:ENL YEATS
Map data
Sample
  • Complex: Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex
    • Complex: ENL YEATS domain
      • Protein or peptide: Protein ENL
    • Complex: DDB1dB/CRBN
      • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]nonan-7-yl]sulfonylamino]piperidin-1-yl]ethylcarbamoyl]phenyl]-~{N}-cyclobutyl-imidazo[1,2-a]pyridine-6-carboxamide
KeywordsMammalian / ENL YEATS / CRBN / dHTC1 / CIP / targeted protein degradation / LIGASE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / : / RNA Polymerase II Pre-transcription Events / transcription elongation factor complex ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / : / RNA Polymerase II Pre-transcription Events / transcription elongation factor complex / positive regulation of protein-containing complex assembly / fibrillar center / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / protein ubiquitination / chromatin binding / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / nucleoplasm / metal ion binding / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
AF-9, ANC1 homology domain / : / ANC1 homology domain (AHD) / : / YEATS superfamily / YEATS family / YEATS domain profile. / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain ...AF-9, ANC1 homology domain / : / ANC1 homology domain (AHD) / : / YEATS superfamily / YEATS family / YEATS domain profile. / 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
Similarity search - Domain/homology
Protein ENL / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCheong H / Hunkeler M / Fischer ES
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214608 United States
CitationJournal: bioRxiv / Year: 2025
Title: High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.
Authors: James B Shaum / Miquel Muñoz I Ordoño / Erica A Steen / Daniela V Wenge / Hakyung Cheong / Moritz Hunkeler / Eric M Bilotta / Zoe Rutter / Paige A Barta / Abby M Thornhill / Natalia ...Authors: James B Shaum / Miquel Muñoz I Ordoño / Erica A Steen / Daniela V Wenge / Hakyung Cheong / Moritz Hunkeler / Eric M Bilotta / Zoe Rutter / Paige A Barta / Abby M Thornhill / Natalia Milosevich / Lauren M Hargis / Jordan Janowski / Timothy R Bishop / Trever R Carter / Bryce da Camara / Matthias Hinterndorfer / Lucas Dada / Wen-Ji He / Fabian Offensperger / Hirotake Furihata / Sydney R Schweber / Charlie Hatton / Yanhe Wen / Benjamin F Cravatt / Keary M Engle / Katherine A Donovan / Bruno Melillo / Seiya Kitamura / Alessio Ciulli / Scott A Armstrong / Eric S Fischer / Georg E Winter / Michael A Erb
Abstract: Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of ...Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.
History
DepositionOct 4, 2024-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateNov 19, 2025-
Current statusNov 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47174.png

Downloads & links

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Map

FileDownload / File: emd_47174.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 256 pix.
= 235.52 Å		0.92 Å/pix.
x 256 pix.
= 235.52 Å		0.92 Å/pix.
x 256 pix.
= 235.52 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.119131066 - 0.2203039
Average (Standard dev.)0.00018670727 (±0.004170458)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 235.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47174_msk_1.map
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Additional map: DeepEMhancer

Fileemd_47174_additional_1.map
AnnotationDeepEMhancer
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Additional map: #1

Fileemd_47174_additional_2.map
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Half map: #1

Fileemd_47174_half_map_1.map
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Half map: #2

Fileemd_47174_half_map_2.map
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Sample components

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Entire : Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex

EntireName: Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex
Components
  • Complex: Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex
    • Complex: ENL YEATS domain
      • Protein or peptide: Protein ENL
    • Complex: DDB1dB/CRBN
      • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]nonan-7-yl]sulfonylamino]piperidin-1-yl]ethylcarbamoyl]phenyl]-~{N}-cyclobutyl-imidazo[1,2-a]pyridine-6-carboxamide

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Supramolecule #1: Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex

SupramoleculeName: Ternary complex of dHTC1 induced DDB1dB/CRBN, ENL YEATS complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: ENL YEATS domain bound to full length CRBN bound via degrader dHTC1
Molecular weightTheoretical: 169 KDa

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Supramolecule #2: ENL YEATS domain

SupramoleculeName: ENL YEATS domain / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.2 KDa

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Supramolecule #3: DDB1dB/CRBN

SupramoleculeName: DDB1dB/CRBN / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 151 KDa

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Details: N terminal FLAG tagged CRBN / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.144594 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDYKDDDDKS AVDENLYFQG GGRGGSAHIV MVDAYKPTKG GSGMAGEGDQ QDAAHNMGNH LPLLPAESEE EDEMEVEDQD SKEAKKPNI INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK D RTFAVLAY ...String:
MDYKDDDDKS AVDENLYFQG GGRGGSAHIV MVDAYKPTKG GSGMAGEGDQ QDAAHNMGNH LPLLPAESEE EDEMEVEDQD SKEAKKPNI INFDTSLPTS HTYLGADMEE FHGRTLHDDD SCQVIPVLPQ VMMILIPGQT LPLQLFHPQE VSMVRNLIQK D RTFAVLAY SNVQEREAQF GTTAEIYAYR EEQDFGIEIV KVKAIGRQRF KVLELRTQSD GIQQAKVQIL PECVLPSTMS AV QLESLNK CQIFPSKPVS REDQCSYKWW QKYQKRKFHC ANLTSWPRWL YSLYDAETLM DRIKKQLREW DENLKDDSLP SNP IDFSYR VAACLPIDDV LRIQLLKIGS AIQRLRCELD IMNKCTSLCC KQCQETEITT KNEIFSLSLC GPMAAYVNPH GYVH ETLTV YKACNLNLIG RPSTEHSWFP GYAWTVAQCK ICASHIGWKF TATKKDMSPQ KFWGLTRSAL LPTIPDTEDE ISPDK VILC L

UniProtKB: Protein cereblon

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Macromolecule #2: Protein ENL

MacromoleculeName: Protein ENL / type: protein_or_peptide / ID: 2 / Details: C terminal His tag / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.225002 KDa
Recombinant expressionOrganism: Escherichia coli B (bacteria)
SequenceString:
MDNQCTVQVR LELGHRAQLR KKPTTEGFTH DWMVFVRGPE QCDIQHFVEK VVFWLHDSFP KPRRVCKEPP YKVEESGYAG FIMPIEVHF KNKEEPRKVC FTYDLFLNLE GNPPVNHLRC EKLTFNNPTT EFRYKLLRAG GVMVMPEGAH HHHHH

UniProtKB: Protein ENL

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]no...

MacromoleculeName: 2-[3-[2-[4-[[(5~{S})-1,3-bis(oxidanylidene)-2,7-diazaspiro[4.4]nonan-7-yl]sulfonylamino]piperidin-1-yl]ethylcarbamoyl]phenyl]-~{N}-cyclobutyl-imidazo[1,2-a]pyridine-6-carboxamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1IQT
Molecular weightTheoretical: 676.786 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

BufferpH: 7.4
Component:
ConcentrationFormulaName
30.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium chloride

Details: 30 mM HEPES/NaOH pH7.4, 150 mM NaCl. DMSO concentrations were kept below 2% (v/v)
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 5 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.039 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283 K / Instrument: LEICA EM GP
Details: Grids were vitrified using a Leica EM GP plunge freezer operated at 90% humidity and 10 C. Grids were first pre-incubated with 4 uL of 10 uM CRBN-agnostic IKZF1_140-196_Q146A,G151N for 1 ...Details: Grids were vitrified using a Leica EM GP plunge freezer operated at 90% humidity and 10 C. Grids were first pre-incubated with 4 uL of 10 uM CRBN-agnostic IKZF1_140-196_Q146A,G151N for 1 minute and then blotted from behind for 4 s. Immediately, 4 uL of mixturewas applied to the grids before blotting for 4 s and plunging into liquid ethane at -181 C.
DetailsParticles from two grids were merged for this data set. The grids differed in protein concentration. Grid1: DDB1dB/CRBN:dHTC1:ENL YEATS of 1.4, 14, 2.8 uM Grid2: DDB1dB/CRBN:dHTC1:ENL YEATS of 1.6, 16, 3.2 uM

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 2 / Number real images: 22883 / Average exposure time: 2.87 sec. / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 9955887
CTF correctionSoftware - Name: cryoSPARC (ver. 4.5.3) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5.3) / Number images used: 185312
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final 3D classificationNumber classes: 12 / Software - Name: cryoSPARC (ver. 4.5.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

8tnq

chain_id: B, source_name: PDB, initial_model_type: experimental model

6phy

chain_id: A, source_name: PDB, initial_model_type: experimental model
RefinementOverall B value: 119.8
Output model

PDB-9dur:
Cryo-EM Structure of CRBN:dHTC1:ENL YEATS

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