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- PDB-7ea8: Human SETD2 bound to a nucleosome containing oncohistone mutations -

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Entry
Database: PDB / ID: 7ea8
TitleHuman SETD2 bound to a nucleosome containing oncohistone mutations
Components
  • (601-DNA) x 2
  • Histone H2A type 1-D
  • Histone H2B type 2-E
  • Histone H3.3
  • Histone H4
  • Histone-lysine N-methyltransferase SETD2
KeywordsGENE REGULATION / SETD2 / methyltransferase / nucleosome / H3.3K36M
Function / homology
Function and homology information


mesoderm morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / coronary vasculature morphogenesis / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / embryonic placenta morphogenesis / histone H3K36 trimethyltransferase activity / pericardium development ...mesoderm morphogenesis / morphogenesis of a branching structure / peptidyl-lysine trimethylation / coronary vasculature morphogenesis / cell migration involved in vasculogenesis / microtubule cytoskeleton organization involved in mitosis / [histone H3]-lysine36 N-trimethyltransferase / embryonic placenta morphogenesis / histone H3K36 trimethyltransferase activity / pericardium development / regulation of mRNA export from nucleus / stem cell development / histone H3K36 methyltransferase activity / nucleosome organization / response to type I interferon / protein-lysine N-methyltransferase activity / embryonic cranial skeleton morphogenesis / positive regulation of ossification / 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 / forebrain development / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / positive regulation of autophagy / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Deposition of new CENPA-containing nucleosomes at the centromere / Inhibition of DNA recombination at telomere / Meiotic synapsis / RNA Polymerase I Promoter Opening / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / innate immune response in mucosa / DNA methylation / Condensation of Prophase Chromosomes / Transferases; Transferring one-carbon groups; Methyltransferases / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / regulation of cytokinesis / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / stem cell differentiation / Nonhomologous End-Joining (NHEJ) / neural tube closure / RNA Polymerase I Promoter Escape / transcription elongation by RNA polymerase II / 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 / G2/M DNA damage checkpoint / : / NoRC negatively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / B-WICH complex positively regulates rRNA expression / PKMTs methylate histone lysines / Meiotic recombination / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of granulopoiesis / HCMV Early Events / antimicrobial humoral immune response mediated by antimicrobial peptide / structural constituent of chromatin / antibacterial humoral response / UCH proteinases / nucleosome / heterochromatin formation / nucleosome assembly / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / HATs acetylate histones / RUNX1 regulates transcription of genes involved in differentiation of HSCs / chromosome / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / angiogenesis / defense response to virus / Estrogen-dependent gene expression / defense response to Gram-positive bacterium / Ub-specific processing proteases / Amyloid fiber formation / protein heterodimerization activity
Similarity search - Function
Histone-lysine N-methyltransferase SETD2, animal / Set2 Rpb1 interacting domain superfamily / SETD2/Set2, SET domain / Set2 Rpb1 interacting domain / SRI (Set2 Rpb1 interacting) domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / Cysteine-rich motif following a subset of SET domains ...Histone-lysine N-methyltransferase SETD2, animal / Set2 Rpb1 interacting domain superfamily / SETD2/Set2, SET domain / Set2 Rpb1 interacting domain / SRI (Set2 Rpb1 interacting) domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / Cysteine-rich motif following a subset of SET domains / TFIIS/LEDGF domain superfamily / Post-SET domain / Post-SET domain profile. / Histone, subunit A / Histone, subunit A / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / WW domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / : / 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 H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2A type 1-D / Histone H2B type 2-E / Histone-lysine N-methyltransferase SETD2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsJing, H. / Liu, Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32022036 China
National Natural Science Foundation of China (NSFC)31570766 China
National Natural Science Foundation of China (NSFC)U1632130 China
CitationJournal: 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
DepositionMar 6, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 2.0Jul 28, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / struct_conf / struct_ref / struct_ref_seq / struct_sheet_range
Item: _atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id ..._atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
L: Histone-lysine N-methyltransferase SETD2
A: Histone H3.3
B: Histone H4
C: Histone H2A type 1-D
D: Histone H2B type 2-E
E: Histone H3.3
F: Histone H4
G: Histone H2A type 1-D
H: Histone H2B type 2-E
I: 601-DNA
J: 601-DNA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)195,84515
Polymers195,25011
Non-polymers5954
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 9 molecules LAEBFCGDH

#1: Protein Histone-lysine N-methyltransferase SETD2 / HIF-1 / Huntingtin yeast partner B / Huntingtin-interacting protein 1 / HIP-1 / Huntingtin- ...HIF-1 / Huntingtin yeast partner B / Huntingtin-interacting protein 1 / HIP-1 / Huntingtin-interacting protein B / Lysine N-methyltransferase 3A / Protein-lysine N-methyltransferase SETD2 / SET domain-containing protein 2 / hSET2 / p231HBP


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
#2: Protein Histone H3.3


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 Histone H4


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 Histone H2A type 1-D / Histone H2A.3 / Histone H2A/g


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 Histone H2B type 2-E / H2B-clustered histone 21 / Histone H2B-GL105 / Histone H2B.q / H2B/q


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

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DNA chain , 2 types, 2 molecules IJ

#6: DNA chain 601-DNA


Mass: 37436.836 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#7: DNA chain 601-DNA


Mass: 37868.090 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 4 molecules

#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#9: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S

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Details

Has ligand of interestN

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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
1Human SETD2-NCP(H3.3K36M)-SAM complex structureCOMPLEX#1-#70MULTIPLE SOURCES
2Histone-lysine N-methyltransferase SETD2COMPLEX#11RECOMBINANT
3HistoneCOMPLEX#2-#51RECOMBINANT
4DNACOMPLEX#6-#71RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli BL21(DE3) (bacteria)469008
32Escherichia coli BL21(DE3) (bacteria)469008
Buffer solutionpH: 7.5
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: 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 FIELD
Image recordingElectron dose: 1.5625 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.13_2998refinement
PHENIX1.13_2998refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154984 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003613590
ELECTRON MICROSCOPYf_angle_d0.672419375
ELECTRON MICROSCOPYf_chiral_restr0.04282172
ELECTRON MICROSCOPYf_plane_restr0.00581621
ELECTRON MICROSCOPYf_dihedral_angle_d20.73727347

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