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- EMDB-72725: Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-9864... -

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Basic information

Entry
Database: EMDB / ID: EMD-72725
TitleCryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-986458 (local refined), a potent and selective BCL6 ligand directed degrader (LDD)
Map data
Sample
  • Complex: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458
    • Protein or peptide: B-cell lymphoma 6 protein
    • Protein or peptide: Protein cereblon
  • Ligand: (3R)-3-(6-{[(3R,4R)-1-{5-chloro-4-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]pyrimidin-2-yl}-3-methylpiperidin-4-yl]amino}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Ligand: ZINC ION
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 plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / negative regulation of isotype switching to IgE isotypes / 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 plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / negative regulation of isotype switching to IgE isotypes / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / germinal center formation / negative regulation of mononuclear cell proliferation / plasma cell differentiation / paraspeckles / regulation of immune system process / pyramidal neuron differentiation / type 2 immune response / T-helper 2 cell differentiation / negative regulation of Rho protein signal transduction / positive regulation of regulatory T cell differentiation / positive regulation of cell motility / negative regulation of B cell apoptotic process / limb development / FOXO-mediated transcription of cell death genes / Cul4A-RING E3 ubiquitin ligase complex / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / regulation of T cell proliferation / regulation of cell differentiation / B cell proliferation / locomotory exploration behavior / negative regulation of cellular senescence / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / regulation of immune response / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / erythrocyte development / Rho protein signal transduction / positive regulation of B cell proliferation / positive regulation of neuron differentiation / regulation of cytokine production / transcription corepressor binding / cell-matrix adhesion / cell motility / positive regulation of protein-containing complex assembly / 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 / sequence-specific DNA binding / DNA-binding transcription factor binding / Potential therapeutics for SARS / transcription by RNA polymerase II / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / positive regulation of apoptotic process / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / inflammatory response / 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 / membrane / nucleus / 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: 3.09 Å
AuthorsZhu J / Fang W / Pagarigan B
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: J Med Chem / Year: 2026
Title: Discovery of BMS-986458, a Potent and Selective B-Cell Lymphoma 6 Protein Ligand-Directed Degrader, for the Treatment of B-Cell Non-Hodgkin Lymphoma.
Authors: Deborah S Mortensen / Hunter P Shunatona / Natalie Holmberg-Douglas / Jayce Rhodes / Diogo Da Silva / Jim Gamez / Matt Groza / Jinyi Zhu / Andy Christoforou / Scott A Johnson / Godrej ...Authors: Deborah S Mortensen / Hunter P Shunatona / Natalie Holmberg-Douglas / Jayce Rhodes / Diogo Da Silva / Jim Gamez / Matt Groza / Jinyi Zhu / Andy Christoforou / Scott A Johnson / Godrej Khambatta / Rama Krishna Narla / Roshan Y Nimje / Dehua Huang / Dharmpal S Dodd / Jennifer Griffin / Giulianna Miseo / Brandon Whitefield / Dahlia R Weiss / James Rader / Elif Kuzu / Jim Leisten / Chon Lai / Lihong Shi / Joselyn Del Rosario / Deepak Dalvie / Mark Rolfe / Christoph W Zapf / Peter Belmont / Matt Alexander / Neil Bence / Lynda Groocock /
Abstract: B-cell lymphoma 6 protein (BCL6) is an oncogenic driver dysregulated and overexpressed in subtypes of high-risk non-Hodgkin lymphoma (NHL). Development of agents that induce the targeted degradation ...B-cell lymphoma 6 protein (BCL6) is an oncogenic driver dysregulated and overexpressed in subtypes of high-risk non-Hodgkin lymphoma (NHL). Development of agents that induce the targeted degradation of BCL6 would offer a promising novel therapeutic approach. For this purpose, we employed ligand-directed degraders, heterobifunctional molecules linking a BCL6-binding ligand to a cereblon recruiter, enabling cereblon-mediated BCL6 degradation. Through a focused optimization effort, we identified highly potent BCL6 degraders, culminating in the selection of BMS-986458 for clinical development. BMS-986458 induces rapid cereblon-dependent BCL6 degradation while sparing known CRBN neosubstrates such as CK1α, GSPT1, Aiolos, Ikaros, or SALL4. Oral administration of BMS-986458 results in dose-dependent pharmacokinetics, pharmacodynamics, and significant antitumor efficacy in mouse models of lymphoma. A potential first-in-class agent, BMS-986458, is currently being evaluated in a phase 1/2 clinical trial (NCT06090539) for patients with relapsed/refractory NHL.
History
DepositionSep 15, 2025-
Header (metadata) releaseFeb 18, 2026-
Map releaseFeb 18, 2026-
UpdateFeb 18, 2026-
Current statusFeb 18, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72725.png

Downloads & links

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Map

FileDownload / File: emd_72725.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 280 pix.
= 264.6 Å		0.95 Å/pix.
x 280 pix.
= 264.6 Å		0.95 Å/pix.
x 280 pix.
= 264.6 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: 0.0685
Minimum - Maximum-0.13138153 - 0.2617204
Average (Standard dev.)-0.00029424755 (±0.0038798454)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 264.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72725_msk_1.map
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Additional map: Sharpened map by deepEMhancer

Fileemd_72725_additional_1.map
AnnotationSharpened map by deepEMhancer
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Half map: #1

Fileemd_72725_half_map_1.map
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Half map: #2

Fileemd_72725_half_map_2.map
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Sample components

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Entire : ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458

EntireName: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458
Components
  • Complex: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458
    • Protein or peptide: B-cell lymphoma 6 protein
    • Protein or peptide: Protein cereblon
  • Ligand: (3R)-3-(6-{[(3R,4R)-1-{5-chloro-4-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]pyrimidin-2-yl}-3-methylpiperidin-4-yl]amino}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Ligand: ZINC ION

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Supramolecule #1: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458

SupramoleculeName: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: BCL6 BTB domain and CRBN/DDB1 was mixed with BMS-986458 in 1:1:2 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 (E. coli)
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: (3R)-3-(6-{[(3R,4R)-1-{5-chloro-4-[(1-methyl-2-oxo-2,3-dihydro-1H...

MacromoleculeName: (3R)-3-(6-{[(3R,4R)-1-{5-chloro-4-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)amino]pyrimidin-2-yl}-3-methylpiperidin-4-yl]amino}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1CTU
Molecular weightTheoretical: 628.124 Da

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 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: 11500 / Average exposure time: 3.66 sec. / Average electron dose: 40.0 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: 1.9000000000000001 µm / Nominal defocus min: 1.3 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: 19671274
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

9q03

Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 202942
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 3 / Avg.num./class: 101000 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9q03


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9ya9:
Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-986458 (local refined), a potent and selective BCL6 ligand directed degrader (LDD)

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