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- PDB-9ya9: Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-9864... -

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Basic information

Entry
Database: PDB / ID: 9ya9
TitleCryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BMS-986458 (local refined), a potent and selective BCL6 ligand directed degrader (LDD)
Components
  • B-cell lymphoma 6 protein
  • Protein cereblon
KeywordsLIGASE / Cereblon / BCL6 / LDD / degrader / E3
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsZhu, J. / Fang, W. / Pagarigan, B.
Funding support1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Primary map / Data content type: Primary map / 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: B-cell lymphoma 6 protein
B: B-cell lymphoma 6 protein
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,1395
Polymers86,4463
Non-polymers6942
Water00
1


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

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Components

#1: Protein B-cell lymphoma 6 protein / BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing ...BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing protein 27 / Zinc finger protein 51


Mass: 16431.863 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51 / Plasmid: pMAL-c5x / Cell (production host): BL21 DE3 / Production host: Escherichia coli (E. coli) / References: UniProt: P41182
#2: Protein Protein cereblon


Mass: 53581.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: Chemical ChemComp-A1CTU / (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


Mass: 628.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H34ClN9O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


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

ComponentName: ternary complex of BCL6-CRBN-DDB1 with an LDD BMS-986458
Type: COMPLEX
Details: BCL6 BTB domain and CRBN/DDB1 was mixed with BMS-986458 in 1:1:2 ratio
Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.162 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)1
2200 mMsodium chlorideNaCl1
31 mMtris(2-carboxyethyl)phosphine1
40.25 %Dimethyl sulfoxide1
50.001 %Lauryl Maltose Neopentyl Glycol1
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 1900 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.66 sec. / Electron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 11500

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2Topazparticle selection
3EPUimage acquisition
5cryoSPARCCTF correction
8Cootmodel fitting
12cryoSPARCclassification
13cryoSPARC3D reconstruction
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 19671274
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 202942 / Algorithm: FOURIER SPACE / Num. of class averages: 2 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: pdb_00009q03

Accession code: pdb_00009q03 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.09 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034753
ELECTRON MICROSCOPYf_angle_d0.5086437
ELECTRON MICROSCOPYf_dihedral_angle_d12.7241806
ELECTRON MICROSCOPYf_chiral_restr0.041728
ELECTRON MICROSCOPYf_plane_restr0.005815

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