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Yorodumi- PDB-7ea8: Human SETD2 bound to a nucleosome containing oncohistone mutations -
+Open data
-Basic information
Entry | Database: PDB / ID: 7ea8 | ||||||||||||
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Title | Human SETD2 bound to a nucleosome containing oncohistone mutations | ||||||||||||
Components |
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Keywords | GENE REGULATION / SETD2 / methyltransferase / nucleosome / H3.3K36M | ||||||||||||
Function / homology | Function and homology information mesoderm morphogenesis / coronary vasculature morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / embryonic placenta morphogenesis / regulation of mRNA export from nucleus ...mesoderm morphogenesis / coronary vasculature morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / embryonic placenta morphogenesis / regulation of mRNA export from nucleus / pericardium development / nucleosome organization / stem cell development / histone H3K36 methyltransferase activity / protein-lysine N-methyltransferase activity / response to type I interferon / positive regulation of ossification / embryonic cranial skeleton morphogenesis / response to alkaloid / regulation of protein localization to chromatin / response to metal ion / histone H3 methyltransferase activity / regulation of double-strand break repair via homologous recombination / endodermal cell differentiation / positive regulation of interferon-alpha production / alpha-tubulin binding / mismatch repair / Replacement of protamines by nucleosomes in the male pronucleus / positive regulation of autophagy / Packaging Of Telomere Ends / forebrain development / 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 / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / Meiotic synapsis / Transferases; Transferring one-carbon groups; Methyltransferases / RNA Polymerase I Promoter Opening / Assembly of the ORC complex at the origin of replication / DNA methylation / Condensation of Prophase Chromosomes / HCMV Late Events / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / innate immune response in mucosa / PRC2 methylates histones and DNA / regulation of cytokinesis / Defective pyroptosis / neural tube closure / HDACs deacetylate histones / stem cell differentiation / transcription elongation by RNA polymerase II / RNA Polymerase I Promoter Escape / 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 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / NoRC negatively regulates rRNA expression / G2/M DNA damage checkpoint / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / Metalloprotease DUBs / response to organic cyclic compound / PKMTs methylate histone lysines / RMTs methylate histone arginines / Meiotic recombination / Pre-NOTCH Transcription and Translation / nucleosome assembly / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / UCH proteinases / nucleosome / antimicrobial humoral immune response mediated by antimicrobial peptide / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromosome / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Processing of DNA double-strand break ends / HATs acetylate histones / antibacterial humoral response / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / defense response to virus / angiogenesis / Oxidative Stress Induced Senescence / Estrogen-dependent gene expression / Ub-specific processing proteases / defense response to Gram-positive bacterium / Amyloid fiber formation / protein heterodimerization activity / regulation of DNA-templated transcription / DNA binding / extracellular space / extracellular exosome / nucleoplasm Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||||||||
Authors | Jing, H. / Liu, Y. | ||||||||||||
Funding support | China, 3items
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Citation | Journal: Cell Discov / Year: 2021 Title: Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations. Authors: Yingying Liu / Yanjun Zhang / Han Xue / Mi Cao / Guohui Bai / Zongkai Mu / Yanli Yao / Shuyang Sun / Dong Fang / Jing Huang / Abstract: Substitution of lysine 36 with methionine in histone H3.3 (H3.3K36M) is an oncogenic mutation that inhibits SETD2-mediated histone H3K36 tri-methylation in tumors. To investigate how the oncohistone ...Substitution of lysine 36 with methionine in histone H3.3 (H3.3K36M) is an oncogenic mutation that inhibits SETD2-mediated histone H3K36 tri-methylation in tumors. To investigate how the oncohistone mutation affects the function of SETD2 at the nucleosome level, we determined the cryo-EM structure of human SETD2 associated with an H3.3K36M nucleosome and cofactor S-adenosylmethionine (SAM), and revealed that SETD2 is attached to the N-terminal region of histone H3 and the nucleosome DNA at superhelix location 1, accompanied with the partial unwrapping of nucleosome DNA to expose the SETD2-binding site. These structural features were also observed in the previous cryo-EM structure of the fungal Set2-nucleosome complex. By contrast with the stable association of SETD2 with the H3.3K36M nucleosome, the EM densities of SETD2 could not be observed on the wild-type nucleosome surface, suggesting that the association of SETD2 with wild-type nucleosome might be transient. The linker histone H1, which stabilizes the wrapping of nucleosome DNA at the entry/exit sites, exhibits an inhibitory effect on the activities of SETD2 and displays inversely correlated genome distributions with that of the H3K36me3 marks. Cryo-EM analysis of yeast H3K36 methyltransferase Set2 complexed with nucleosomes further revealed evolutionarily conserved structural features for nucleosome recognition in eukaryotes, and provides insights into the mechanism of activity regulation. These findings have advanced our understanding of the structural basis for the tumorigenesis mechanism of the H3.3K36M mutation and highlight the effect of nucleosome conformation on the regulation of histone modification. | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7ea8.cif.gz | 349.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7ea8.ent.gz | 252.9 KB | Display | PDB format |
PDBx/mmJSON format | 7ea8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ea/7ea8 ftp://data.pdbj.org/pub/pdb/validation_reports/ea/7ea8 | HTTPS FTP |
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-Related structure data
Related structure data | 31040MC 7ea5C 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 LAEBFCGDH
#1: Protein | Mass: 28580.467 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SETD2, HIF1, HYPB, KIAA1732, KMT3A, SET2, HSPC069 / Production host: Escherichia coli BL21(DE3) (bacteria) References: UniProt: Q9BYW2, [histone H3]-lysine36 N-trimethyltransferase, Transferases; Transferring one-carbon groups; Methyltransferases | ||||||
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#2: Protein | Mass: 11657.632 Da / Num. of mol.: 2 / Mutation: K36M Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) #3: Protein | Mass: 8853.342 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) #4: Protein | Mass: 11351.226 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2AC7, H2AFG, HIST1H2AD / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P20671 #5: Protein | Mass: 13820.045 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC21, H2BFQ, HIST2H2BE / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q16778 |
-DNA chain , 2 types, 2 molecules IJ
#6: DNA chain | Mass: 37436.836 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
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#7: DNA chain | Mass: 37868.090 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
-Non-polymers , 2 types, 4 molecules
#8: Chemical | #9: Chemical | ChemComp-SAM / | |
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-Details
Has ligand of interest | N |
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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 |
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Specimen | Conc.: 0.3 mg/ml / 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 FIELDBright-field microscopy |
Image recording | Electron dose: 1.5625 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154984 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library | ||||||||||||||||||||||||
Refine LS restraints |
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