+Open data
-Basic information
Entry | Database: PDB / ID: 7e8d | ||||||
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Title | NSD2 E1099K mutant bound to nucleosome | ||||||
Components |
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Keywords | GENE REGULATION / chromatin / epigenetics / histone methyltransferase / muitiple myeloma | ||||||
Function / homology | Function and homology information atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / histone H3K36 dimethyltransferase activity / histone H4K20 methyltransferase activity / regulation of double-strand break repair via nonhomologous end joining / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / membranous septum morphogenesis / atrial septum primum morphogenesis ...atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / histone H3K36 dimethyltransferase activity / histone H4K20 methyltransferase activity / regulation of double-strand break repair via nonhomologous end joining / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / membranous septum morphogenesis / atrial septum primum morphogenesis / histone H3K36 methyltransferase activity / histone H3 methyltransferase activity / negative regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Deposition of new CENPA-containing nucleosomes at the centromere / nucleosomal DNA binding / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / telomere organization / Meiotic synapsis / Interleukin-7 signaling / RNA Polymerase I Promoter Opening / epigenetic regulation of gene expression / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / bone development / Assembly of the ORC complex at the origin of replication / SUMOylation of chromatin organization proteins / DNA methylation / Regulation of endogenous retroelements by KRAB-ZFP proteins / Condensation of Prophase Chromosomes / HCMV Late Events / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / innate immune response in mucosa / PRC2 methylates histones and DNA / Defective pyroptosis / HDACs deacetylate histones / RNA Polymerase I Promoter Escape / lipopolysaccharide binding / Nonhomologous End-Joining (NHEJ) / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / G2/M DNA damage checkpoint / HDMs demethylate histones / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / heterochromatin formation / PKMTs methylate histone lysines / Metalloprotease DUBs / Meiotic recombination / Pre-NOTCH Transcription and Translation / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / UCH proteinases / antimicrobial humoral immune response mediated by antimicrobial peptide / nucleosome / double-strand break repair / nucleosome assembly / E3 ubiquitin ligases ubiquitinate target proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / antibacterial humoral response / chromatin organization / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Factors involved in megakaryocyte development and platelet production / HATs acetylate histones / gene expression / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / defense response to Gram-negative bacterium / methylation / Estrogen-dependent gene expression / killing of cells of another organism / sequence-specific DNA binding / chromosome, telomeric region / Ub-specific processing proteases / defense response to Gram-positive bacterium / cadherin binding / protein heterodimerization activity / Amyloid fiber formation / chromatin binding / regulation of DNA-templated transcription / chromatin / nucleolus Similarity search - Function | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||
Authors | Sengoku, T. / Sato, K. / Nishizawa, T. / Nureki, O. / Ogata, K. | ||||||
Citation | Journal: Nat Commun / Year: 2021 Title: Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2. Authors: Ko Sato / Amarjeet Kumar / Keisuke Hamada / Chikako Okada / Asako Oguni / Ayumi Machiyama / Shun Sakuraba / Tomohiro Nishizawa / Osamu Nureki / Hidetoshi Kono / Kazuhiro Ogata / Toru Sengoku / Abstract: Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is ...Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2. | ||||||
History |
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-Structure visualization
Movie |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7e8d.cif.gz | 353.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7e8d.ent.gz | 264.8 KB | Display | PDB format |
PDBx/mmJSON format | 7e8d.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7e8d_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 7e8d_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 7e8d_validation.xml.gz | 41.8 KB | Display | |
Data in CIF | 7e8d_validation.cif.gz | 67.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/e8/7e8d ftp://data.pdbj.org/pub/pdb/validation_reports/e8/7e8d | HTTPS FTP |
-Related structure data
Related structure data | 31015MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 5 types, 9 molecules AEBFCGDHK
#1: Protein | Mass: 15307.984 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: H3C1, H3FA, HIST1H3A, H3C2, H3FL, HIST1H3B, H3C3, H3FC HIST1H3C, H3C4, H3FB, HIST1H3D, H3C6, H3FD, HIST1H3E, H3C7, H3FI, HIST1H3F, H3C8, H3FH, HIST1H3G, H3C10, H3FK, HIST1H3H, H3C11, H3FF, ...Gene: H3C1, H3FA, HIST1H3A, H3C2, H3FL, HIST1H3B, H3C3, H3FC HIST1H3C, H3C4, H3FB, HIST1H3D, H3C6, H3FD, HIST1H3E, H3C7, H3FI, HIST1H3F, H3C8, H3FH, HIST1H3G, H3C10, H3FK, HIST1H3H, H3C11, H3FF, HIST1H3I, H3C12, H3FJ, HIST1H3J Production host: Escherichia coli (E. coli) / References: UniProt: P68431 #2: Protein | Mass: 11263.231 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, H4/E, ...Gene: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, H4/E, H4FE, HIST1H4K, H4/D, H4FD, HIST1H4L, H4/K, H4FK, HIST2H4A, H4/N, H4F2, H4FN, HIST2H4, HIST2H4B, H4/O, H4FO, HIST4H4 Production host: Escherichia coli (E. coli) / References: UniProt: P62805 #3: Protein | Mass: 13990.342 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: H2AC11, H2AFP, HIST1H2AG, H2AC13, H2AFC, HIST1H2AI, H2AC15, H2AFD, HIST1H2AK, H2AC16, H2AFI, HIST1H2AL, H2AC17, H2AFN, HIST1H2AM Production host: Escherichia coli (E. coli) / References: UniProt: P0C0S8 #4: Protein | Mass: 13804.045 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC11, H2BFR, HIST1H2BJ / Production host: Escherichia coli (E. coli) / References: UniProt: P06899 #7: Protein | | Mass: 28986.139 Da / Num. of mol.: 1 / Mutation: E1099K Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Production host: Escherichia coli (E. coli) References: UniProt: O96028, [histone H3]-lysine36 N-dimethyltransferase |
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-DNA chain , 2 types, 2 molecules IJ
#5: DNA chain | Mass: 56841.191 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others) |
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#6: DNA chain | Mass: 57392.527 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: synthetic construct (others) |
-Non-polymers , 2 types, 4 molecules
#8: Chemical | #9: Chemical | ChemComp-SFG / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: NSD2-nucleosome complex / Type: COMPLEX / Entity ID: #1-#7 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 136108 / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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