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- EMDB-72178: Cereblon Ternary Complex with Blimp1 and compound 5 -

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Basic information

Entry
Database: EMDB / ID: EMD-72178
TitleCereblon Ternary Complex with Blimp1 and compound 5
Map dataFocused Refinement
Sample
  • Complex: Cereblon Ternary Complex with Blimp1 and compound 5
    • Protein or peptide: PR domain zinc finger protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: N-({(4R)-7-[(1S)-2-amino-1-(4-bromo-2-methylphenyl)-2-oxoethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl}methyl)-13-{4-[(3R)-2,6-dioxopiperidin-3-yl]anilino}tridecanamide
KeywordsLiganded Cereblon Ligase Substrate / LIGASE
Function / homology
Function and homology information


regulation of extrathymic T cell differentiation / regulation of NK T cell differentiation / sebum secreting cell proliferation / morphogenesis of a branching structure / retinal bipolar neuron differentiation / regulation of natural killer cell differentiation / maternal placenta development / Specification of primordial germ cells / trophoblast giant cell differentiation / eye photoreceptor cell development ...regulation of extrathymic T cell differentiation / regulation of NK T cell differentiation / sebum secreting cell proliferation / morphogenesis of a branching structure / retinal bipolar neuron differentiation / regulation of natural killer cell differentiation / maternal placenta development / Specification of primordial germ cells / trophoblast giant cell differentiation / eye photoreceptor cell development / negative regulation of monoatomic ion transmembrane transport / histone methyltransferase binding / intestinal epithelial cell development / heart valve development / coronary vasculature development / STAT3 nuclear events downstream of ALK signaling / Regulation of TP53 Expression / artery morphogenesis / aorta development / ventricular septum development / Cul4A-RING E3 ubiquitin ligase complex / germ cell development / locomotory exploration behavior / cell fate commitment / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / Transferases; Transferring one-carbon groups; Methyltransferases / post-embryonic development / methyltransferase activity / promoter-specific chromatin binding / kidney development / positive regulation of protein-containing complex assembly / DNA-binding transcription repressor activity, RNA polymerase II-specific / sequence-specific double-stranded DNA binding / regulation of cell population proliferation / methylation / gene expression / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / adaptive immune response / transmembrane transporter binding / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / innate immune response / positive regulation of gene expression / regulation of transcription by RNA polymerase II / nucleolus / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
PR domain zinc finger protein 1 / PRDM1, PR/SET domain / PR domain zinc finger protein 2, PR domain / : / 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 ...PR domain zinc finger protein 1 / PRDM1, PR/SET domain / PR domain zinc finger protein 2, PR domain / : / 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 / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain profile. / SET domain superfamily / SET domain / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type
Similarity search - Domain/homology
PR domain zinc finger protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWatson ER / Lander GC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J Med Chem / Year: 2025
Title: Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders.
Authors: Bryan J Simmons / Lynda Groocock / Jesus Moreno / David S Peters / Meredith E Hughes / Vijay Veeravalli / Jennifer M Crawford / Matthew Chalkley / Mark Griffith / Melissa Plooster / Bo Hu / ...Authors: Bryan J Simmons / Lynda Groocock / Jesus Moreno / David S Peters / Meredith E Hughes / Vijay Veeravalli / Jennifer M Crawford / Matthew Chalkley / Mark Griffith / Melissa Plooster / Bo Hu / Jim Gamez / Jim Leisten / Michael J Barnes / Jason Chinn / Gauri Deb / Hardik Modi / Madhu Katepalli / Dahlia Weiss / Walter Won / Zhenghang Sun / Shan Yu / Cameron Reid / Andrew F Donnell / Ling Li / Edmond R Watson / Sophie Perrin-Ninkovic / Lihong Shi / Rama Krishna Narla / Christoph W Zapf / Neil Bence / Antonia Lopez-Girona / Jennifer R Riggs /
Abstract: B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. ...B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Multiple myeloma (MM) is a plasma cell malignancy wherein the BLIMP-1 regulon remains critical to support basal cell functions, such as an elevated metabolic state and immunoglobulin production that underlie disease manifestation and tumor cell proliferation. It is predicted that perturbation of BLIMP-1 will significantly impact tumor cell homeostasis and ultimately reduce MM cell survival. Herein, we describe the discovery and optimization of the first orally bioavailable BLIMP-1 heterobifunctional ligand-directed degrader (LDD) and demonstration of the expected antitumor response and immunomodulatory biology following BLIMP-1 degradation using preclinical in vivo MM models.
History
DepositionAug 15, 2025-
Header (metadata) releaseJan 14, 2026-
Map releaseJan 14, 2026-
UpdateJan 14, 2026-
Current statusJan 14, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72178.png

Downloads & links

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Map

FileDownload / File: emd_72178.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused Refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 256 pix.
= 271.36 Å		1.06 Å/pix.
x 256 pix.
= 271.36 Å		1.06 Å/pix.
x 256 pix.
= 271.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.229
Minimum - Maximum-1.8736446 - 2.4102898
Average (Standard dev.)-0.00020252922 (±0.029855698)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 271.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Full particle refinement

Fileemd_72178_additional_1.map
AnnotationFull particle refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Focused Refinement unsharpened

Fileemd_72178_additional_2.map
AnnotationFocused Refinement unsharpened
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Additional map: DeepEMhanced Map

Fileemd_72178_additional_3.map
AnnotationDeepEMhanced Map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap 2

Fileemd_72178_half_map_1.map
Annotationhalfmap 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap 1

Fileemd_72178_half_map_2.map
Annotationhalfmap 1
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Cereblon Ternary Complex with Blimp1 and compound 5

EntireName: Cereblon Ternary Complex with Blimp1 and compound 5
Components
  • Complex: Cereblon Ternary Complex with Blimp1 and compound 5
    • Protein or peptide: PR domain zinc finger protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: N-({(4R)-7-[(1S)-2-amino-1-(4-bromo-2-methylphenyl)-2-oxoethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl}methyl)-13-{4-[(3R)-2,6-dioxopiperidin-3-yl]anilino}tridecanamide

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Supramolecule #1: Cereblon Ternary Complex with Blimp1 and compound 5

SupramoleculeName: Cereblon Ternary Complex with Blimp1 and compound 5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: PR domain zinc finger protein 1

MacromoleculeName: PR domain zinc finger protein 1 / type: protein_or_peptide / ID: 1 / Details: 37-222 / Number of copies: 1 / Enantiomer: LEVO
EC number: Transferases; Transferring one-carbon groups; Methyltransferases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.86551 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
GSKMDMEDAD MTLWTEAEFE EKCTYIVNDH PWDSGADGGT SVQAEASLPR NLLFKYATNS EEVIGVMSKE YIPKGTRFGP LIGEIYTND TVPKNANRKY FWRIYSRGEL HHFIDGFNEE KSNWMRYVNP AHSPREQNLA ACQNGMNIYF YTIKPIPANQ E LLVWYCRD FAERLHYPYP GELTMMNLTQ

UniProtKB: PR domain zinc finger protein 1

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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: 50.603676 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNVQ EREAQFGTTA EIYAYREEQD FGIEIVKVKA I GRQRFKVL ...String:
MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNVQ EREAQFGTTA EIYAYREEQD FGIEIVKVKA I GRQRFKVL ELRTQSDGIQ QAKVQILPEC VLPSTMSAVQ LESLNKCQIF PSKPVSREDQ CSYKWWQKYQ KRKFHCANLT SW PRWLYSL YDAETLMDRI KKQLREWDEN LKDDSLPSNP IDFSYRVAAC LPIDDVLRIQ LLKIGSAIQR LRCELDIMNK CTS LCCKQC QETEITTKNE IFSLSLCGPM AAYVNPHGYV HETLTVYKAC NLNLIGRPST EHSWFPGYAW TVAQCKICAS HIGW KFTAT KKDMSPQKFW GLTRSALLPT IPDTEDEISP DKVILCL

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: N-({(4R)-7-[(1S)-2-amino-1-(4-bromo-2-methylphenyl)-2-oxoethyl]-5...

MacromoleculeName: N-({(4R)-7-[(1S)-2-amino-1-(4-bromo-2-methylphenyl)-2-oxoethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl}methyl)-13-{4-[(3R)-2,6-dioxopiperidin-3-yl]anilino}tridecanamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1CN1
Molecular weightTheoretical: 776.805 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

Concentration0.5 mg/mL
BufferpH: 7
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / 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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 174443
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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