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- EMDB-30453: NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP -

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Basic information

Entry
Database: EMDB / ID: EMD-30453
TitleNSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP
Map data
SampleNSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP:
Histone H3, H4, H2A and H2B / DNA / NSD2 / Histone H3 / Histone H4 / Histone H2A / Histone H2B / (nucleic-acidNucleic acid) x 2 / Histone-lysine N-methyltransferase NSD2 / (ligand) x 2
Function / homology
Function and homology information


atrial septum secundum morphogenesis / dermal bone morphogenesis / fin development / [histone H3]-lysine36 N-dimethyltransferase / histone methyltransferase activity (H4-K20 specific) / regulation of double-strand break repair via nonhomologous end joining / atrial septum primum morphogenesis / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / membranous septum morphogenesis ...atrial septum secundum morphogenesis / dermal bone morphogenesis / fin development / [histone H3]-lysine36 N-dimethyltransferase / histone methyltransferase activity (H4-K20 specific) / regulation of double-strand break repair via nonhomologous end joining / atrial septum primum morphogenesis / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / membranous septum morphogenesis / histone methyltransferase activity (H3-K36 specific) / bone development / DNA-templated transcription, initiation / positive regulation of JNK cascade / nucleosome / chromatin / double-strand break repair via nonhomologous end joining / signaling receptor activity / positive regulation of I-kappaB kinase/NF-kappaB signaling / sequence-specific DNA binding / protein heterodimerization activity / chromatin binding / regulation of transcription, DNA-templated / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / plasma membrane / metal ion binding / nucleus / cytoplasm
Histone H3/CENP-A / High mobility group box domain / Histone H2B / SET domain / Zinc finger, RING-type / Histone H4 / Zinc finger, PHD-type / Histone H2A / Post-SET domain / TATA box binding protein associated factor (TAF) ...Histone H3/CENP-A / High mobility group box domain / Histone H2B / SET domain / Zinc finger, RING-type / Histone H4 / Zinc finger, PHD-type / Histone H2A / Post-SET domain / TATA box binding protein associated factor (TAF) / AWS domain / Histone H2A/H2B/H3 / Histone-fold / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / Zinc finger, PHD-type, conserved site / Zinc finger, PHD-finger / Histone H4, conserved site / Histone H2A, C-terminal domain / Histone H2A conserved site / CENP-T/Histone H4, histone fold / High mobility group box domain superfamily / NSD, Cys-His rich domain / PWWP domain
Histone-lysine N-methyltransferase NSD2 / Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H2A / Histone H2B / Histone H3
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human) / Xenopus tropicalis (tropical clawed frog)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsLi W / Tian W / Yuan G / Deng P / Gozani O / Patel D / Wang Z
Funding support China, United States, 6 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31870725 China
Other governmentFundamental Research Funds for the Central Universities (2017EYT19) China
National Natural Science Foundation of China (NSFC)31570729 China
National Institutes of Health/National Library of Medicine (NIH/NLM)R01GM079641 United States
Other governmentMemorial Sloan-Kettering Cancer Center Core grant P30CA008748 United States
Other governmentBasic Research grant from Shenzhen government (JCYJ20180302174213122) China
CitationJournal: Nature / Year: 2020
Title: Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases.
Authors: Wanqiu Li / Wei Tian / Gang Yuan / Pujuan Deng / Deepanwita Sengupta / Zhongjun Cheng / Yinghua Cao / Jiahao Ren / Yan Qin / Yuqiao Zhou / Yulin Jia / Or Gozani / Dinshaw J Patel / Zhanxin Wang /
Abstract: Histone methyltransferases of the nuclear receptor-binding SET domain protein (NSD) family, including NSD1, NSD2 and NSD3, have crucial roles in chromatin regulation and are implicated in oncogenesis. ...Histone methyltransferases of the nuclear receptor-binding SET domain protein (NSD) family, including NSD1, NSD2 and NSD3, have crucial roles in chromatin regulation and are implicated in oncogenesis. NSD enzymes exhibit an autoinhibitory state that is relieved by binding to nucleosomes, enabling dimethylation of histone H3 at Lys36 (H3K36). However, the molecular basis that underlies this mechanism is largely unknown. Here we solve the cryo-electron microscopy structures of NSD2 and NSD3 bound to mononucleosomes. We find that binding of NSD2 and NSD3 to mononucleosomes causes DNA near the linker region to unwrap, which facilitates insertion of the catalytic core between the histone octamer and the unwrapped segment of DNA. A network of DNA- and histone-specific contacts between NSD2 or NSD3 and the nucleosome precisely defines the position of the enzyme on the nucleosome, explaining the specificity of methylation to H3K36. Intermolecular contacts between NSD proteins and nucleosomes are altered by several recurrent cancer-associated mutations in NSD2 and NSD3. NSDs that contain these mutations are catalytically hyperactive in vitro and in cells, and their ectopic expression promotes the proliferation of cancer cells and the growth of xenograft tumours. Together, our research provides molecular insights into the nucleosome-based recognition and histone-modification mechanisms of NSD2 and NSD3, which could lead to strategies for therapeutic targeting of proteins of the NSD family.
Validation ReportPDB-ID: 7cro

SummaryFull reportAbout validation report
History
DepositionAug 14, 2020-
Header (metadata) releaseOct 21, 2020-
Map releaseOct 21, 2020-
UpdateJan 13, 2021-
Current statusJan 13, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cro
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30453.png

Downloads & links

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Map

FileDownload / File: emd_30453.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 216 pix.
= 233.28 Å		1.08 Å/pix.
x 216 pix.
= 233.28 Å		1.08 Å/pix.
x 216 pix.
= 233.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018 / Movie #1: 0.02
Minimum - Maximum-0.07492122 - 0.13057263
Average (Standard dev.)0.0005944858 (±0.005741942)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions216216216
Spacing216216216
CellA=B=C: 233.28001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z216216216
origin x/y/z0.0000.0000.000
length x/y/z233.280233.280233.280
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ304304304
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS216216216
D min/max/mean-0.0750.1310.001

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Supplemental data

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Sample components

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Entire NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP

EntireName: NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP
Number of components: 13

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Component #1: protein, NSD2 bearing E1099K/T1150A dual mutation in complex with...

ProteinName: NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP
Recombinant expression: No
MassExperimental: 300 kDa

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Component #2: protein, Histone H3, H4, H2A and H2B

ProteinName: Histone H3, H4, H2A and H2B / Recombinant expression: No
SourceSpecies: Xenopus laevis (African clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #3: protein, DNA

ProteinName: DNA / Recombinant expression: No
SourceSpecies: Xenopus laevis (African clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #4: protein, NSD2

ProteinName: NSD2 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Baculovirus transfer vector pFASTBAC1

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Component #5: protein, Histone H3

ProteinName: Histone H3 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 15.259855 kDa
SourceSpecies: Xenopus laevis (African clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #6: protein, Histone H4

ProteinName: Histone H4 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 11.263231 kDa
SourceSpecies: Xenopus laevis (African clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #7: protein, Histone H2A

ProteinName: Histone H2A / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 13.978241 kDa
SourceSpecies: Xenopus laevis (African clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #8: protein, Histone H2B

ProteinName: Histone H2B / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 13.524752 kDa
SourceSpecies: Xenopus tropicalis (tropical clawed frog)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #9: nucleic-acid, DNA (168-MER)

nucleic acidName: DNA (168-MER) / Class: DNA / Structure: OTHER / Synthetic: No
Sequence: (DA)(DT)(DC)(DG)(DG)(DG)(DT)(DG)(DA)(DT) (DG)(DC)(DC)(DC)(DG)(DA)(DT)(DC)(DC)(DC) (DC)(DT)(DG)(DG)(DA)(DG)(DA)(DA)(DT)(DC) (DC)(DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA) (DG)(DG)(DC)(DC)(DG)(DC) ...Sequence:
(DA)(DT)(DC)(DG)(DG)(DG)(DT)(DG)(DA)(DT) (DG)(DC)(DC)(DC)(DG)(DA)(DT)(DC)(DC)(DC) (DC)(DT)(DG)(DG)(DA)(DG)(DA)(DA)(DT)(DC) (DC)(DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA) (DG)(DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA)(DC)(DA)(DG)(DC)(DT)(DC)(DT)(DA)(DG) (DC)(DA)(DC)(DC)(DG)(DC)(DT)(DT)(DA)(DA) (DA)(DC)(DG)(DC)(DA)(DC)(DG)(DT)(DA)(DC) (DG)(DC)(DG)(DC)(DT)(DG)(DT)(DC)(DC)(DC) (DC)(DC)(DG)(DC)(DG)(DT)(DT)(DT)(DT)(DA) (DA)(DC)(DC)(DG)(DC)(DC)(DA)(DA)(DG)(DG) (DG)(DG)(DA)(DT)(DT)(DA)(DC)(DT)(DC)(DC) (DC)(DT)(DA)(DG)(DT)(DC)(DT)(DC)(DC)(DA) (DG)(DG)(DC)(DA)(DC)(DG)(DT)(DG)(DT)(DC) (DA)(DG)(DA)(DT)(DA)(DT)(DA)(DT)(DA)(DC) (DA)(DT)(DC)(DC)(DT)(DG)(DT)(DT)(DC)(DC) (DA)(DG)(DT)(DG)(DC)(DC)(DG)(DG)(DT)(DG) (DT)(DC)(DG)(DC)(DG)(DA)(DT)
MassTheoretical: 57.488551 kDa
SourceSpecies: Xenopus laevis (African clawed frog)

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Component #10: nucleic-acid, DNA (168-MER)

nucleic acidName: DNA (168-MER) / Class: DNA / Structure: OTHER / Synthetic: No
Sequence: (DA)(DT)(DC)(DG)(DC)(DG)(DA)(DC)(DA)(DC) (DC)(DG)(DG)(DC)(DA)(DC)(DT)(DG)(DG)(DA) (DA)(DC)(DA)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC) ...Sequence:
(DA)(DT)(DC)(DG)(DC)(DG)(DA)(DC)(DA)(DC) (DC)(DG)(DG)(DC)(DA)(DC)(DT)(DG)(DG)(DA) (DA)(DC)(DA)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC)(DC)(DT)(DG)(DG) (DA)(DG)(DA)(DC)(DT)(DA)(DG)(DG)(DG)(DA) (DG)(DT)(DA)(DA)(DT)(DC)(DC)(DC)(DC)(DT) (DT)(DG)(DG)(DC)(DG)(DG)(DT)(DT)(DA)(DA) (DA)(DA)(DC)(DG)(DC)(DG)(DG)(DG)(DG)(DG) (DA)(DC)(DA)(DG)(DC)(DG)(DC)(DG)(DT)(DA) (DC)(DG)(DT)(DG)(DC)(DG)(DT)(DT)(DT)(DA) (DA)(DG)(DC)(DG)(DG)(DT)(DG)(DC)(DT)(DA) (DG)(DA)(DG)(DC)(DT)(DG)(DT)(DC)(DT)(DA) (DC)(DG)(DA)(DC)(DC)(DA)(DA)(DT)(DT)(DG) (DA)(DG)(DC)(DG)(DG)(DC)(DC)(DT)(DC)(DG) (DG)(DC)(DA)(DC)(DC)(DG)(DG)(DG)(DA)(DT) (DT)(DC)(DT)(DC)(DC)(DA)(DG)(DG)(DG)(DG) (DA)(DT)(DC)(DG)(DG)(DG)(DC)(DA)(DT)(DC) (DA)(DC)(DC)(DC)(DG)(DA)(DT)
MassTheoretical: 57.982918 kDa
SourceSpecies: Xenopus laevis (African clawed frog)

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Component #11: protein, Histone-lysine N-methyltransferase NSD2

ProteinName: Histone-lysine N-methyltransferase NSD2 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 79.688844 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Baculovirus transfer vector pFASTBAC1

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Component #12: ligand, S-ADENOSYLMETHIONINE

LigandName: S-ADENOSYLMETHIONINES-Adenosyl methionine / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.398437 kDa

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Component #13: ligand, ZINC ION

LigandName: ZINC ION / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 6.540905 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 0.3 mg/mL / pH: 7.5
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 281 K / Humidity: 100 %
Details: blotted for 3 s before being plunged into liquid ethane.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD / Energy filter: GIF Bioquantum
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 71116
3D reconstructionResolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

7cro

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