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- PDB-9y60: Crystal structure of NSD2 PWWP1 domain in complex with (6R)-6-(3,... -

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Basic information

Entry
Database: PDB / ID: 9y60
TitleCrystal structure of NSD2 PWWP1 domain in complex with (6R)-6-(3,5-dichlorophenyl)morpholin-3-one (ligand 2)
ComponentsHistone-lysine N-methyltransferase NSD2
KeywordsTRANSFERASE / NSD2 / PWWP1 / binder / methyltransferase
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 / histone H3K36 methyltransferase activity / histone H3 methyltransferase activity / Nonhomologous End-Joining (NHEJ) / 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 / chromatin binding / regulation of DNA-templated transcription / nucleolus / chromatin / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / 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 / Cysteine-rich motif following a subset of SET domains / 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 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.023 Å
AuthorsZhu, J. / Pagarigan, B.E. / Fang, W. / Clayton, T.
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)20,0072
Polymers19,7611
Non-polymers2461
Water1,35175
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area9870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.652, 51.652, 152.219
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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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: 19760.605 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: Chemical ChemComp-A1CSP / (6R)-6-(3,5-dichlorophenyl)morpholin-3-one


Mass: 246.090 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H9Cl2NO2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.65 Å3/Da / Density % sol: 53.61 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: Reservoir: 20% PEG4000, 0.1 M Tris, pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 13, 2018
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.023→20.042 Å / Num. obs: 8308 / % possible obs: 92.7 % / Redundancy: 12.2 % / Biso Wilson estimate: 41.07 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.133 / Rpim(I) all: 0.04 / Rrim(I) all: 0.139 / Net I/σ(I): 11.1
Reflection shellResolution: 2.023→2.269 Å / Redundancy: 10.3 % / Rmerge(I) obs: 2.539 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 415 / CC1/2: 0.542 / Rpim(I) all: 0.827 / Rrim(I) all: 2.675 / % possible all: 78.1

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (21-NOV-2022)refinement
PHASERphasing
PDB_EXTRACTdata extraction
XDSdata reduction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.023→20.04 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.91 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.43 / SU Rfree Blow DPI: 0.276
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2725 430 5.18 %RANDOM
Rwork0.2206 ---
obs0.2234 8308 58.5 %-
Displacement parametersBiso mean: 60.71 Å2
Baniso -1Baniso -2Baniso -3
1-3.0906 Å20 Å20 Å2
2--3.0906 Å20 Å2
3----6.1812 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.023→20.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1290 0 15 75 1380
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082556HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.974601HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d729SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes427HARMONIC5
X-RAY DIFFRACTIONt_it1342HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion17.85
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion168SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2024SEMIHARMONIC4
LS refinement shellResolution: 2.023→2.269 Å
RfactorNum. reflection% reflection
Rfree0.4126 -6.57 %
Rwork0.3266 370 -
obs--10.01 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10-7.6365-5.230816.62223.700923.19920.7786-1.0204-0.330.6198-0.85410.37390.61951.05260.07550.2966-0.0312-0.0802-0.2459-0.0154-0.403120.459-10.3552-3.2077
22.5404-4.83260.63794.8673-2.79.13350.0625-0.0302-0.1319-0.9326-0.14460.55311.6327-0.87180.08210.3748-0.26460.0617-0.0942-0.0849-0.20516.2191-6.50277.7471
34.08510.6042-2.10682.6427-0.693911.1572-0.07560.112-0.0273-0.218-0.1256-0.49960.90040.03260.2012-0.05870.00480.07590.0629-0.0016-0.066621.21272.843711.0743
47.15832.2189-0.60410.2467-4.29398.9265-0.1999-0.1514-0.1015-0.2809-0.1479-0.91921.0879-0.08150.3479-0.0426-0.00470.04540.0534-0.0126-0.215619.8788-0.055713.8259
53.6739-1.48458.73126.0361-7.334524.9426-0.2743-1.3428-0.6990.95280.76840.21.2394-1.302-0.49420.1686-0.0310.1559-0.14880.1371-0.221316.234-6.650327.5137
66.14272.11478.73124.1832-1.17316.60030.573-0.6497-0.59470.04860.0752-1.3521.28520.4847-0.64820.0750.0873-0.06190.35650.1579-0.005527.6652-0.893932.1082
72.26260.43091.77493.21053.611613.4172-0.035-0.00860.13810.16810.00220.17580.0735-1.54770.0328-0.2927-0.11060.0010.4547-0.0211-0.19097.57355.595518.3207
811.047-5.962-0.045714.8799-1.899924.94630.48531.63271.2569-0.7336-0.521-1.0194-1.24070.42090.0357-0.15780.12120.06020.13460.1185-0.105313.786315.68918.3664
920.2471-7.2512-8.731218.35037.58712.3561-0.01791.24941.16230.4149-0.8656-0.9475-0.31680.08190.8835-0.37520.0720.03310.17320.0244-0.07273.582615.546622.4927
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|203 - 212}
2X-RAY DIFFRACTION2{A|213 - 228}
3X-RAY DIFFRACTION3{A|229 - 271}
4X-RAY DIFFRACTION4{A|272 - 286}
5X-RAY DIFFRACTION5{A|287 - 299}
6X-RAY DIFFRACTION6{A|300 - 315}
7X-RAY DIFFRACTION7{A|316 - 344}
8X-RAY DIFFRACTION8{A|345 - 356}
9X-RAY DIFFRACTION9{A|357 - 371}

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