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- EMDB-30457: Native NSD3 bound to 187-bp nucleosome -

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Basic information

Entry
Database: EMDB / ID: EMD-30457
TitleNative NSD3 bound to 187-bp nucleosome
Map data
SampleCryo-EM structure of the native NSD3 bound to 187-bp nucleosome:
Histone H3, H4, H2A, H2B / DNA / native NSD3 / Histone H3 / Histone H4 / Histone H2A / Histone H2B / (nucleic-acidNucleic acid) x 2 / Histone-lysine N-methyltransferase NSD3 / (ligand) x 2
Function / homology
Function and homology information


dermal bone morphogenesis / fin development / [histone H3]-lysine4 N-dimethyltransferase / [histone H3]-lysine27 N-dimethyltransferase / transcription regulator activator activity / histone methyltransferase activity (H3-K36 specific) / histone methylation / histone-lysine N-methyltransferase activity / positive regulation of histone H3-K36 trimethylation / DNA-templated transcription, initiation ...dermal bone morphogenesis / fin development / [histone H3]-lysine4 N-dimethyltransferase / [histone H3]-lysine27 N-dimethyltransferase / transcription regulator activator activity / histone methyltransferase activity (H3-K36 specific) / histone methylation / histone-lysine N-methyltransferase activity / positive regulation of histone H3-K36 trimethylation / DNA-templated transcription, initiation / nucleosome / protein heterodimerization activity / chromatin / regulation of transcription, DNA-templated / positive regulation of transcription, DNA-templated / DNA binding / nucleoplasm / metal ion binding / nucleus
Histone H4 / Histone-fold / Histone H2B / PWWP domain / Histone H3/CENP-A / Histone H2A / Post-SET domain / TATA box binding protein associated factor (TAF) / AWS domain / Histone H2A/H2B/H3 ...Histone H4 / Histone-fold / Histone H2B / PWWP domain / Histone H3/CENP-A / Histone H2A / Post-SET domain / TATA box binding protein associated factor (TAF) / AWS domain / Histone H2A/H2B/H3 / SET domain / Zinc finger, PHD-type / 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 / NSD, Cys-His rich domain
Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H2A / Histone H2B / Histone H3 / Histone-lysine N-methyltransferase NSD3
Biological speciesXenopus laevis (African clawed frog) / synthetic construct (others) / Homo sapiens (human) / Xenopus tropicalis (tropical clawed frog)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.48 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: 2021
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 ReportSummary, Full report, XML, About validation report
History
DepositionAug 14, 2020-
Header (metadata) releaseOct 21, 2020-
Map releaseOct 21, 2020-
UpdateMar 3, 2021-
Current statusMar 3, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.017
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.017
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7crr
  • Surface level: 0.017
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30457.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
Contour LevelBy AUTHOR: 0.017 / Movie #1: 0.017
Minimum - Maximum-0.07091129 - 0.12928021
Average (Standard dev.)0.00048626965 (±0.0051194495)
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-0.0710.1290.000

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Supplemental data

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Sample components

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Entire Cryo-EM structure of the native NSD3 bound to 187-bp nucleosome

EntireName: Cryo-EM structure of the native NSD3 bound to 187-bp nucleosome
Number of components: 13

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Component #1: protein, Cryo-EM structure of the native NSD3 bound to 187-bp nuc...

ProteinName: Cryo-EM structure of the native NSD3 bound to 187-bp nucleosome
Recombinant expression: No
MassExperimental: 300 kDa

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

ProteinName: Histone H3, H4, H2A, 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: synthetic construct (others)

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Component #4: protein, native NSD3

ProteinName: native NSD3 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #5: protein, Histone H3

ProteinName: Histone H3 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 15.223779 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: synthetic construct (others)

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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: synthetic construct (others)

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Component #11: protein, Histone-lysine N-methyltransferase NSD3

ProteinName: Histone-lysine N-methyltransferase NSD3 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 85.484312 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: 61058
3D reconstructionResolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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