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- PDB-9y61: Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in comp... -

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Basic information

Entry
Database: PDB / ID: 9y61
TitleCryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader
Components
  • Histone-lysine N-methyltransferase NSD2
  • Protein cereblon
KeywordsLIGASE / Cereblon / degrader / DDB1 / NSD2 / PWWP1 / LDD
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZhu, J. / Pagarigan, B.E. / Fang, W.
Funding support1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 15, 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

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase NSD2
B: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,2384
Polymers73,4012
Non-polymers8372
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 Histone-lysine N-methyltransferase NSD2 / Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / ...Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / Protein trithorax-5 / Wolf-Hirschhorn syndrome candidate 1 protein


Mass: 19818.707 Da / Num. of mol.: 1 / Fragment: UNP residues 202-368
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O96028, [histone H3]-lysine36 N-dimethyltransferase
#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-A1CSQ / 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


Mass: 771.748 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H49Cl2FN6O5 / 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 NSD2-PWWP1:NSD2-LDD:CRBN:DDB1 / Type: COMPLEX
Details: NSD2 PWWP1 domain, CRBN/DDB1 complex, and NSD2-LDD in 1:1:3 ratio
Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.166 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
110 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)1
2240 mMsodium chlorideNaCl1
33 mMtris(2-carboxyethyl)phosphine1
40.5 %Dimethyl sulfoxide1
50.001 %Lauryl Maltose Neopentyl Glycol1
SpecimenConc.: 3.5 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 R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K / Details: blot time 4 sec blot force 4

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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: 75000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.49 sec. / Electron dose: 33.85 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 14049

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 14824032
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127545 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 8D81

8d81


Accession code: 8D81 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033604
ELECTRON MICROSCOPYf_angle_d0.5514882
ELECTRON MICROSCOPYf_dihedral_angle_d12.3641384
ELECTRON MICROSCOPYf_chiral_restr0.04532
ELECTRON MICROSCOPYf_plane_restr0.004616

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