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- PDB-7cro: NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP -

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Basic information

Entry
Database: PDB / ID: 7cro
TitleNSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCP
Components
  • (DNA (168-MER)) x 2
  • Histone H2A
  • Histone H2B
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase NSD2
KeywordsGENE REGULATION / nucleosome complex / histone methyltransferase / DNA
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 / regulation of establishment of protein localization / atrial septum primum morphogenesis / 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 / regulation of establishment of protein localization / atrial septum primum morphogenesis / 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 / structural constituent of chromatin / double-strand break repair / nucleosome / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / methylation / Processing of DNA double-strand break ends / sequence-specific DNA binding / protein heterodimerization activity / chromatin binding / chromatin / nucleolus / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / metal ion binding / nucleus / cytoplasm
Similarity search - Function
: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / NSD Cys-His rich domain ...: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / NSD Cys-His rich domain / 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 superfamily / SET domain / SET domain profile. / SET domain / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Zinc finger, PHD-type, conserved site / PHD-finger / Ring finger / 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. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Histone H3 signature 1. / Zinc finger, PHD-type / PHD zinc finger / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Zinc finger, RING-type / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Zinc finger, FYVE/PHD-type / Histone-fold / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone-lysine N-methyltransferase NSD2 / Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H2A / Histone H2B / Histone H3
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: 3.75 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 Library of Medicine (NIH/NLM)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 / Data collection ...Atomic model / 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_poly_seq_scheme / pdbx_struct_sheet_hbond / 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_ec / _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_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _struct_sheet_range.beg_auth_asym_id / _struct_sheet_range.beg_auth_comp_id / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.beg_label_asym_id / _struct_sheet_range.beg_label_comp_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_asym_id / _struct_sheet_range.end_auth_comp_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_asym_id / _struct_sheet_range.end_label_comp_id / _struct_sheet_range.end_label_seq_id / _struct_sheet_range.id / _struct_sheet_range.sheet_id
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

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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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 NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)303,73515
Polymers303,14011
Non-polymers5954
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area58790 Å2
ΔGint-406 kcal/mol
Surface area104500 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 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: 79688.844 Da / Num. of mol.: 1 / Mutation: E1099K, T1150A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Production host: Baculovirus transfer vector pFASTBAC1
References: UniProt: O96028, [histone H3]-lysine36 N-dimethyltransferase

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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 / S-Adenosyl methionine


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

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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
1NSD2 bearing E1099K/T1150A dual mutation in complex with 187-bp NCPCOMPLEX#1-#70RECOMBINANT
2Histone H3, H4, H2A and H2BCOMPLEX#1-#41RECOMBINANT
3DNACOMPLEX#5-#61RECOMBINANT
4NSD2COMPLEX#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 / Details: The sample was monodisperse.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K
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
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 32

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71116 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00615754
ELECTRON MICROSCOPYf_angle_d0.64422731
ELECTRON MICROSCOPYf_dihedral_angle_d22.5358748
ELECTRON MICROSCOPYf_chiral_restr0.042572
ELECTRON MICROSCOPYf_plane_restr0.0041721

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