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- PDB-7ea5: Yeast Set2 bound to a nucleosome containing oncohistone mutations -

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Basic information

Entry
Database: PDB / ID: 7ea5
TitleYeast Set2 bound to a nucleosome containing oncohistone mutations
Components
  • (601-DNA) x 2
  • Histone H2A
  • Histone H2B
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase, H3 lysine-36 specificHistone methyltransferase
KeywordsGENE REGULATION / methyltransferase / Set2 / nucleosome / H3K36M mutation
Function / homology
Function and homology information


[histone H3]-lysine36 N-trimethyltransferase / histone H3K36 methyltransferase activity / structural constituent of chromatin / nucleosome / chromosome / protein heterodimerization activity / regulation of DNA-templated transcription / DNA binding / nucleus
Similarity search - Function
WW domain / Histone-lysine N-methyltransferase, Set2, fungi / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / Set2 Rpb1 interacting domain / Set2 Rpb1 interacting domain superfamily / SRI (Set2 Rpb1 interacting) domain / SETD2/Set2, SET domain / AWS domain / AWS domain / AWS domain profile. ...WW domain / Histone-lysine N-methyltransferase, Set2, fungi / Histone-lysine N-methyltransferase (EC 2.1.1.43) family profile. / Set2 Rpb1 interacting domain / Set2 Rpb1 interacting domain superfamily / SRI (Set2 Rpb1 interacting) domain / SETD2/Set2, SET 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. / WW domain superfamily / Domain with 2 conserved Trp (W) residues / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / WW domain / SET domain / 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 H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B / Histone H3 / Histone-lysine N-methyltransferase, H3 lysine-36 specific / Histone H2A
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Saccharomyces cerevisiae (brewer's yeast)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 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

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Histone H3
B: Histone H4
C: Histone H2A
D: Histone H2B
E: Histone H3
F: Histone H4
G: Histone H2A
H: Histone H2B
I: 601-DNA
J: 601-DNA
K: Histone-lysine N-methyltransferase, H3 lysine-36 specific
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,01315
Polymers201,41811
Non-polymers5954
Water0
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 AEBFCGDHK

#1: Protein Histone H3 /


Mass: 11847.916 Da / Num. of mol.: 2 / Mutation: K37M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: XELAEV_18002543mg / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A310TTQ1
#2: Protein Histone H4 /


Mass: 8853.342 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: H4 / Production host: Escherichia coli (E. coli)
#3: Protein Histone H2A /


Mass: 11494.393 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog)
Gene: h2ac14.L, h2ac14, hist1h2aj, LOC494591, XELAEV_18003602mg
Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZJ8
#4: Protein Histone H2B /


Mass: 10406.954 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: XELAEV_18032685mg / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: A0A1L8FQA5
#7: Protein Histone-lysine N-methyltransferase, H3 lysine-36 specific / Histone methyltransferase / SET domain-containing protein 2


Mass: 26699.021 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: SCNYR20_0009003900, SCP684_0009003900 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A0A6V8RR65, [histone H3]-lysine36 N-trimethyltransferase

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain 601-DNA


Mass: 44521.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain 601-DNA


Mass: 44992.648 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 / S-Adenosyl methionine


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

ComponentName: The Set2-nucleosome(H3K36M)complex structure / Type: COMPLEX / Entity ID: #1-#7 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Source (recombinant)Organism: Escherichia coli (E. coli)
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 FIELDBright-field microscopy
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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 225474 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003514612
ELECTRON MICROSCOPYf_angle_d0.635320967
ELECTRON MICROSCOPYf_chiral_restr0.04042357
ELECTRON MICROSCOPYf_plane_restr0.00531663
ELECTRON MICROSCOPYf_dihedral_angle_d21.43077783

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