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- PDB-7crp: NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp N... -

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Basic information

Entry
Database: PDB / ID: 7crp
TitleNSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (1:1 binding mode)
Components
  • (DNA (168-MER)) x 2
  • Histone H2A
  • Histone H2B
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase NSD3
KeywordsGENE REGULATION / nucleosome complex histone methyltransferase
Function / homology
Function and homology information


[histone H3]-lysine4 N-dimethyltransferase / [histone H3]-lysine27 N-dimethyltransferase / histone H3K4 dimethyltransferase activity / histone H3K27 dimethyltransferase activity / histone H3K27 trimethyltransferase activity / histone H3K36 methyltransferase activity / transcription regulator activator activity / histone H3 methyltransferase activity / PKMTs methylate histone lysines / structural constituent of chromatin ...[histone H3]-lysine4 N-dimethyltransferase / [histone H3]-lysine27 N-dimethyltransferase / histone H3K4 dimethyltransferase activity / histone H3K27 dimethyltransferase activity / histone H3K27 trimethyltransferase activity / histone H3K36 methyltransferase activity / transcription regulator activator activity / histone H3 methyltransferase activity / PKMTs methylate histone lysines / structural constituent of chromatin / nucleosome / nucleosome assembly / methylation / protein heterodimerization activity / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / DNA binding / nucleoplasm / nucleus / metal ion binding
Similarity search - Function
: / : / : / : / : / : / 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 ...: / : / : / : / : / : / 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. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Zinc finger, PHD-type, conserved site / Zinc finger PHD-type signature. / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Zinc finger, FYVE/PHD-type / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H2A / Histone H2B / Histone H3 / Histone-lysine N-methyltransferase NSD3
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Xenopus tropicalis (tropical clawed frog)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLi, W. / Tian, W. / Yuan, G. / Deng, P. / Gozani, O. / Patel, D. / Wang, Z.
Funding support China, United States, 6items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31870725 China
National Natural Science Foundation of China (NSFC)31570729 China
Other governmentFundamental Research Funds for the Central Universities (2017EYT19) China
Other governmentMemorial Sloan-Kettering Cancer Center Core grant P30CA008748 United States
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)R01GM079641 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.
History
DepositionAug 14, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.name
Revision 2.0Jan 20, 2021Group: Atomic model / Author supporting evidence ...Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / em_software / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_instance_feature / pdbx_poly_seq_scheme / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_validate_torsion / struct_conf / struct_conn / struct_ref_seq_dif / struct_sheet / struct_sheet_order / struct_sheet_range
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.group_PDB / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _em_software.category / _entity.formula_weight / _entity.pdbx_mutation / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly_seq.mon_id / _entity_src_gen.pdbx_gene_src_gene / _pdbx_entity_instance_feature.auth_comp_id / _pdbx_entity_instance_feature.comp_id / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_assembly_prop.value / _pdbx_validate_torsion.phi
Description: Sequence discrepancy
Details: The Methionine residues (Met90, Met120) from ChainM and ChainE were replaced with Norleucine (Nle90, Nle120).
Provider: author / Type: Coordinate replacement
Revision 2.1Mar 3, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 2.2Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature / struct_sheet
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification / _struct_sheet.number_strands

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-30455
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Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
M: Histone H3
B: Histone H4
C: Histone H2A
D: Histone H2B
E: Histone H3
F: Histone H4
G: Histone H2A
H: Histone H2B
A: DNA (168-MER)
K: DNA (168-MER)
I: Histone-lysine N-methyltransferase NSD3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)309,50015
Polymers308,90611
Non-polymers5954
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area59420 Å2
ΔGint-410 kcal/mol
Surface area104360 Å2

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Components

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Protein , 5 types, 9 molecules MEBFCGDHI

#1: Protein Histone H3


Mass: 15223.779 Da / Num. of mol.: 2 / Mutation: K36Nle, M90Nle, M120Nle
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: h3c8.S, h3c8, H3l, hist1h3g / Production host: Escherichia coli (E. coli) / References: UniProt: Q92133
#2: Protein Histone H4


Mass: 11263.231 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P62799
#3: Protein Histone H2A


Mass: 13978.241 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: hist1h2aj, LOC494591, XELAEV_18003602mg / Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZJ8, UniProt: P06897*PLUS
#4: Protein Histone H2B


Mass: 13524.752 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus tropicalis (tropical clawed frog)
Gene: h2bc12, hist1h2bk / Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZK7, UniProt: P02281*PLUS
#7: Protein Histone-lysine N-methyltransferase NSD3 / Nuclear SET domain-containing protein 3 / Protein whistle / WHSC1-like 1 isoform 9 with ...Nuclear SET domain-containing protein 3 / Protein whistle / WHSC1-like 1 isoform 9 with methyltransferase activity to lysine / Wolf-Hirschhorn syndrome candidate 1-like protein 1 / WHSC1-like protein 1


Mass: 85454.359 Da / Num. of mol.: 1 / Mutation: E1181K, T1232A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD3, WHSC1L1, DC28 / Production host: Baculovirus transfer vector pFASTBAC1
References: UniProt: Q9BZ95, Transferases; Transferring one-carbon groups; Methyltransferases

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DNA chain , 2 types, 2 molecules AK

#5: DNA chain DNA (168-MER)


Mass: 57488.551 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli)
#6: DNA chain DNA (168-MER)


Mass: 57982.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli)

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Non-polymers , 2 types, 4 molecules

#8: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1NSD3 bearing E1181K/T1232A dual mutation in complex with 187-bp NCP (1:1 binding mode)COMPLEX#1-#70RECOMBINANT
2Histone H3, H4, H2A, H2BCOMPLEX#1-#41RECOMBINANT
3DNACOMPLEX#5-#61RECOMBINANT
4NSD3COMPLEX#71RECOMBINANT
Molecular weightValue: 0.3 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Xenopus laevis (African clawed frog)8355
23Xenopus laevis (African clawed frog)8355
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
34Baculovirus transfer vector pFASTBAC1136645
Buffer solutionpH: 7.5
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording
IDImaging-IDElectron dose (e/Å2)Detector modeFilm or detector model
1150SUPER-RESOLUTIONGATAN K2 SUMMIT (4k x 4k)
2150GATAN K2 SUMMIT (4k x 4k)
3150SUPER-RESOLUTIONGATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215398 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00615773
ELECTRON MICROSCOPYf_angle_d0.69922753
ELECTRON MICROSCOPYf_dihedral_angle_d22.4598787
ELECTRON MICROSCOPYf_chiral_restr0.0422575
ELECTRON MICROSCOPYf_plane_restr0.0051728

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