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- EMDB-72526: Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in comp... -

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Entry
Database: EMDB / ID: EMD-72526
TitleCryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader
Map data
Sample
  • Complex: Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1
    • Protein or peptide: Histone-lysine N-methyltransferase NSD2
    • Protein or peptide: Protein cereblon
  • Ligand: 1-(5-{9-[(4-{2-[(2S,3R)-2-(3,5-dichloro-4-fluorophenyl)-5-oxomorpholin-3-yl]ethyl}piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl}-2-methylphenyl)-1,3-diazinane-2,4-dione
  • Ligand: ZINC ION
KeywordsCereblon / degrader / DDB1 / NSD2 / PWWP1 / LDD / LIGASE
Function / homology
Function and homology information


atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / regulation of double-strand break repair via nonhomologous end joining / histone H4K20 methyltransferase activity / histone H3K36 dimethyltransferase activity / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / atrial septum primum morphogenesis / regulation of establishment of protein localization / membranous septum morphogenesis ...atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / regulation of double-strand break repair via nonhomologous end joining / histone H4K20 methyltransferase activity / histone H3K36 dimethyltransferase activity / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / atrial septum primum morphogenesis / regulation of establishment of protein localization / membranous septum morphogenesis / negative regulation of monoatomic ion transmembrane transport / histone H3K36 methyltransferase activity / histone H3 methyltransferase activity / limb development / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / Nonhomologous End-Joining (NHEJ) / positive regulation of protein-containing complex assembly / bone development / G2/M DNA damage checkpoint / PKMTs methylate histone lysines / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Processing of DNA double-strand break ends / methylation / sequence-specific DNA binding / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / protein ubiquitination / chromatin binding / regulation of DNA-templated transcription / nucleolus / chromatin / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / : ...: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / : / : / : / NSD Cys-His rich domain / Histone-lysine N-methyltransferase NSD-like, PHD zinc finger / Histone-lysine N-methyltransferase NSD-like, variant PHD zinc finger / Histone-lysine N-methyltransferase NSD-like, PHD zinc finger 1 / : / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Cysteine-rich motif following a subset of SET domains / 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) / Post-SET domain / Post-SET domain profile. / HMG (high mobility group) box / HMG boxes A and B DNA-binding domains profile. / high mobility group / High mobility group box domain / High mobility group box domain superfamily / PUA-like superfamily / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain profile. / SET domain superfamily / SET domain / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Ring finger / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Histone-lysine N-methyltransferase NSD2 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZhu J / Pagarigan BE / Fang W
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Blood / Year: 2026
Title: NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma.
Authors: Bo Hu / Jacob Edwards / Hardik Modi / Jim Gamez / Oscar Enrique Echeagaray / Kyle Hess / Yue Ren / Diana Anderson / Marta Larrayoz / Jinyi Zhu / Scott Arne Johnson / Gauri Deb / Diana ...Authors: Bo Hu / Jacob Edwards / Hardik Modi / Jim Gamez / Oscar Enrique Echeagaray / Kyle Hess / Yue Ren / Diana Anderson / Marta Larrayoz / Jinyi Zhu / Scott Arne Johnson / Gauri Deb / Diana Jankeel / Preethi Janardhanan / Jim Leisten / Sophie Peng / Andy Christoforou / Nicholas Stong / Celia Fontanillo / Chad C Bjorklund / Patrick Ryan Hagner / Anita Krithivas Gandhi / Jose A Martínez-Climent / Rama Krishna Narla / Antonia Lopez-Girona / Mark Rolfe / Neil Bence / Deborah S Mortensen / Lynda Groocock /
Abstract: The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of ...The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein isoforms. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Although the NSD2-LDD response is restricted to PWWP1-containining models, collectively this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.
History
DepositionSep 6, 2025-
Header (metadata) releaseJul 15, 2026-
Map releaseJul 15, 2026-
UpdateJul 15, 2026-
Current statusJul 15, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72526.png

Downloads & links

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Map

FileDownload / File: emd_72526.map.gz / Format: CCP4 / Size: 64 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.)
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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0435
Minimum - Maximum-0.11203376 - 0.24757953
Average (Standard dev.)-0.00031984286 (±0.0035611743)
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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Mask #1

Fileemd_72526_msk_1.map
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Half map: #1

Fileemd_72526_half_map_1.map
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Half map: #2

Fileemd_72526_half_map_2.map
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Sample components

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Entire : Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1

EntireName: Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1
Components
  • Complex: Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1
    • Protein or peptide: Histone-lysine N-methyltransferase NSD2
    • Protein or peptide: Protein cereblon
  • Ligand: 1-(5-{9-[(4-{2-[(2S,3R)-2-(3,5-dichloro-4-fluorophenyl)-5-oxomorpholin-3-yl]ethyl}piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl}-2-methylphenyl)-1,3-diazinane-2,4-dione
  • Ligand: ZINC ION

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Supramolecule #1: Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1

SupramoleculeName: Ternary complex NSD2-PWWP1:NSD2-LDD:CRBN:DDB1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: NSD2 PWWP1 domain, CRBN/DDB1 complex, and NSD2-LDD in 1:1:3 ratio
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 166 KDa

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Macromolecule #1: Histone-lysine N-methyltransferase NSD2

MacromoleculeName: Histone-lysine N-methyltransferase NSD2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: [histone H3]-lysine36 N-dimethyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.818707 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MAKKESCPNT GRDKDHLLKY NVGDLVWSKV SGYPWWPCMV SADPLLHSYT KLKGQKKSAR QYHVQFFGDA PERAWIFEKS LVAFEGEGQ FEKLCQESAK QAPTKAEKIK LLKPISGKLR AQWEMGIVQA EEAASMSVEE RKAKFTFLYV GDQLHLNPQV A KEAGIAAE HHHHHH

UniProtKB: Histone-lysine N-methyltransferase NSD2

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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: 1-(5-{9-[(4-{2-[(2S,3R)-2-(3,5-dichloro-4-fluorophenyl)-5-oxomorp...

MacromoleculeName: 1-(5-{9-[(4-{2-[(2S,3R)-2-(3,5-dichloro-4-fluorophenyl)-5-oxomorpholin-3-yl]ethyl}piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl}-2-methylphenyl)-1,3-diazinane-2,4-dione
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1CSQ
Molecular weightTheoretical: 771.748 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

Concentration3.5 mg/mL
BufferpH: 7
Component:
ConcentrationNameFormula
10.0 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)
240.0 mMsodium chlorideNaCl
3.0 mMtris(2-carboxyethyl)phosphine
0.5 %Dimethyl sulfoxide
0.001 %Lauryl Maltose Neopentyl Glycol
GridModel: Quantifoil R0.6/1 / 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 / Details: blot time 4 sec blot force 4.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 14049 / Average exposure time: 3.49 sec. / Average electron dose: 33.85 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: 2.5 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 75000
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: 14824032
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8d81

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 127545
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8d81


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

PDB-9y61:
Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader

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