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- EMDB-30454: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp N... -

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Basic information

Entry
Database: EMDB / ID: EMD-30454
TitleNSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (class2 map)
Map data
Sample
  • Complex: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (class2 map)
    • Complex: 187-bp NCP
    • Complex: NSD3
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 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 Center for Complementary and Integrative Health (NIH/NCCIH)R01GM079641 United States
Other governmentMemorial Sloan-Kettering Cancer Center Core grant P30CA008748 United States
Other governmentBasic Research grant from Shenzhen government to (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.
History
DepositionAug 14, 2020-
Header (metadata) releaseOct 21, 2020-
Map releaseOct 21, 2020-
UpdateOct 21, 2020-
Current statusOct 21, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30454.png

Downloads & links

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Map

FileDownload / File: emd_30454.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: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.07032012 - 0.15619966
Average (Standard dev.)0.00047492562 (±0.005328272)
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-0.0700.1560.000

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Supplemental data

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Sample components

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Entire : NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp N...

EntireName: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (class2 map)
Components
  • Complex: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (class2 map)
    • Complex: 187-bp NCP
    • Complex: NSD3

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Supramolecule #1: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp N...

SupramoleculeName: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (class2 map)
type: complex / ID: 1 / Parent: 0
Molecular weightExperimental: 300 KDa

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Supramolecule #2: 187-bp NCP

SupramoleculeName: 187-bp NCP / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Xenopus laevis (African clawed frog)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #3: NSD3

SupramoleculeName: NSD3 / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Baculovirus transfer vector pFASTBAC1

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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

Concentration0.3 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 132902
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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