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- EMDB-72086: Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760... -

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Basic information

Entry
Database: EMDB / ID: EMD-72086
TitleCryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760 (LDD, local refined)
Map data
Sample
  • Complex: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760
    • Protein or peptide: B-cell lymphoma 6 protein
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: (3R)-3-(6-{4-[(5-chloro-4-{[3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl]amino}pyrimidin-2-yl)(methyl)amino]piperidin-1-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
KeywordsCereblon / BCL6 / LDD / degrader / E3 / LIGASE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation ...negative regulation of monoatomic ion transmembrane transport / regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation / plasma cell differentiation / paraspeckles / germinal center formation / regulation of immune system process / pyramidal neuron differentiation / type 2 immune response / T-helper 2 cell differentiation / positive regulation of regulatory T cell differentiation / positive regulation of cell motility / negative regulation of B cell apoptotic process / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of Rho protein signal transduction / erythrocyte development / FOXO-mediated transcription of cell death genes / locomotory exploration behavior / regulation of cell differentiation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / regulation of T cell proliferation / B cell proliferation / negative regulation of cellular senescence / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / positive regulation of Wnt signaling pathway / regulation of immune response / negative regulation of protein-containing complex assembly / Rho protein signal transduction / positive regulation of B cell proliferation / positive regulation of neuron differentiation / regulation of cytokine production / cell-matrix adhesion / transcription corepressor binding / positive regulation of protein-containing complex assembly / cell motility / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / cell morphogenesis / sequence-specific double-stranded DNA binding / intracellular protein localization / heterochromatin formation / regulation of cell population proliferation / actin cytoskeleton organization / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / DNA-binding transcription factor binding / sequence-specific DNA binding / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / transcription by RNA polymerase II / protein ubiquitination / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / inflammatory response / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / Golgi apparatus / zinc ion binding / nucleoplasm / metal ion binding / identical protein binding / nucleus / membrane / cytoplasm / cytosol
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 / BTB/POZ domain / BTB domain profile. / Zinc finger, C2H2 type / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / SKP1/BTB/POZ domain superfamily / Zinc finger C2H2-type
Similarity search - Domain/homology
B-cell lymphoma 6 protein / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsZhu J / Fang W / Pagarigan B
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: J Med Chem / Year: 2025
Title: Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760.
Authors: Hunter P Shunatona / Natalie Holmberg Douglas / Jayce Rhodes / William Thomas / Diogo Da Silva / Jim Gamez / Matt Groza / Andy Christoforou / Jinyi Zhu / Scott Johnson / Dharmpal Dodd / ...Authors: Hunter P Shunatona / Natalie Holmberg Douglas / Jayce Rhodes / William Thomas / Diogo Da Silva / Jim Gamez / Matt Groza / Andy Christoforou / Jinyi Zhu / Scott Johnson / Dharmpal Dodd / Dehua Huang / Jennifer Griffin / Giulianna Miseo / Brandon Whitefield / Dahlia Weiss / James Rader / Elif Kuzu / Jim Leisten / Joselyn Del Rosario / Lihong Shi / Mary Matyskiela / Philip P Chamberlain / Peter Belmont / Matt Alexander / Christoph W Zapf / Lynda Groocock / Deborah S Mortensen /
Abstract: The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 () is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 ...The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 () is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 were found to be those containing short aminopiperidine linkers in combination with an indazole-based cereblon (CRBN)-binding moiety (CBM). In vitro ADME profiling of potent molecules identified BCL6-760 as an ideal molecule for use in in vivo experiments due to its good passive permeability, solubility, and microsomal stability. Mechanistic studies confirmed that BCL6 degradation is CRBN mediated, and proteomic assessment indicates a clean and selective degradation profile. BCL6-760 exhibited good oral mouse PK and was capable of penetrant and sustained PD effects. At 60 mg/kg BID dosing, BCL6-760 achieves >90% BCL6 reduction and leads to an overall 64% tumor volume reduction in an OCI-LY-1 mouse xenograft efficacy model.
History
DepositionAug 12, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateOct 15, 2025-
Current statusOct 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72086.png

Downloads & links

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Map

FileDownload / File: emd_72086.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.)
0.95 Å/pix.
x 256 pix.
= 241.92 Å		0.95 Å/pix.
x 256 pix.
= 241.92 Å		0.95 Å/pix.
x 256 pix.
= 241.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.945 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0381
Minimum - Maximum-0.114134364 - 0.25040168
Average (Standard dev.)-0.00056750077 (±0.0043707187)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 241.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72086_msk_1.map
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Half map: #1

Fileemd_72086_half_map_1.map
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Half map: #2

Fileemd_72086_half_map_2.map
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Sample components

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Entire : ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760

EntireName: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760
Components
  • Complex: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760
    • Protein or peptide: B-cell lymphoma 6 protein
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: (3R)-3-(6-{4-[(5-chloro-4-{[3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl]amino}pyrimidin-2-yl)(methyl)amino]piperidin-1-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

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Supramolecule #1: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760

SupramoleculeName: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: BCL6 BTB domain and CRBN/DDB1 was mixed with BCL6-760 in 1:1:1 ratio
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 162 KDa

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Macromolecule #1: B-cell lymphoma 6 protein

MacromoleculeName: B-cell lymphoma 6 protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.431863 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
GSLDYKDDDD KENLYFQGAD SCIQFTRHAS DVLLNLNRLR SRDILTDVVI VVSREQFRAH KTVLMACSGL FYSIFTDQLK CNLSVINLD PEINPEGFCI LLDFMYTSRL NLREGNIMAV MATAMYLQME HVVDTCRKFI KASE

UniProtKB: B-cell lymphoma 6 protein

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Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.581984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA ...String:
MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA YREEQDFGIE IVKVKAIGRQ RFKVLELRTQ SDGIQQAKVQ ILPECVLPST MSAVQLESLN KCQIFPSKPV SR EDQCSYK WWQKYQKRKF HCANLTSWPR WLYSLYDAET LMDRIKKQLR EWDENLKDDS LPSNPIDFSY RVAACLPIDD VLR IQLLKI GSAIQRLRCE LDIMNKCTSL CCKQCQETEI TTKNEIFSLS LCGPMAAYVN PHGYVHETLT VYKACNLNLI GRPS TEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL

UniProtKB: Protein cereblon

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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: (3R)-3-(6-{4-[(5-chloro-4-{[3-(3-hydroxy-3-methylbutyl)-1-methyl-...

MacromoleculeName: (3R)-3-(6-{4-[(5-chloro-4-{[3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl]amino}pyrimidin-2-yl)(methyl)amino]piperidin-1-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1CM7
Molecular weightTheoretical: 715.244 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

Concentration4.0 mg/mL
BufferpH: 7
Component:
ConcentrationNameFormula
20.0 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)
200.0 mMsodium chlorideNaCl
1.0 mMtris(2-carboxyethyl)phosphine
0.25 %Dimethyl sulfoxide
0.001 %Lauryl Maltose Neopentyl Glycol
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 10236 / Average exposure time: 3.16 sec. / Average electron dose: 35.18 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 130000
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: 15859703
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

9dqd

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 112568
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 2 / Avg.num./class: 110000 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

9dqd

source_name: PDB, initial_model_type: experimental model

5x9o

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9q03:
Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760 (LDD, local refined)

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