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- PDB-8vnv: PRC2_AJ1-450 bound to H3K36me3 with histone H3 tail engaged -

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Basic information

Entry
Database: PDB / ID: 8vnv
TitlePRC2_AJ1-450 bound to H3K36me3 with histone H3 tail engaged
Components
  • DNA (26-MER)
  • DNA (26-mer)
  • EED
  • H3K36me3-modified histone H3
  • Isoform 2 of Histone-lysine N-methyltransferase EZH2
  • Polycomb protein SUZ12
  • Protein Jumonji
  • RBAP48
  • Zinc finger protein AEBP2
KeywordsGENE REGULATION/DNA / complex / methyltransferase / histone / epigenetics / GENE REGULATION / GENE REGULATION-DNA complex
Function / homology
Function and homology information


hepatocyte homeostasis / regulation of kidney development / cellular response to trichostatin A / negative regulation of striated muscle cell differentiation / regulation of gliogenesis / negative regulation of keratinocyte differentiation / random inactivation of X chromosome / [histone H3]-lysine27 N-trimethyltransferase / response to tetrachloromethane / CAF-1 complex ...hepatocyte homeostasis / regulation of kidney development / cellular response to trichostatin A / negative regulation of striated muscle cell differentiation / regulation of gliogenesis / negative regulation of keratinocyte differentiation / random inactivation of X chromosome / [histone H3]-lysine27 N-trimethyltransferase / response to tetrachloromethane / CAF-1 complex / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / negative regulation of retinoic acid receptor signaling pathway / histone H3K27 trimethyltransferase activity / cerebellar cortex development / primary miRNA binding / histone H3K27 methyltransferase activity / ubiquitin-modified histone reader activity / sex chromatin / positive regulation of cell cycle G1/S phase transition / NURF complex / regulatory ncRNA-mediated heterochromatin formation / cardiac muscle hypertrophy in response to stress / negative regulation of stem cell differentiation / facultative heterochromatin formation / NuRD complex / regulation of cell fate specification / negative regulation of stem cell population maintenance / DNA replication-dependent chromatin assembly / regulation of stem cell differentiation / ESC/E(Z) complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / RSC-type complex / protein-lysine N-methyltransferase activity / oligodendrocyte differentiation / Polo-like kinase mediated events / chromatin silencing complex / Transcription of E2F targets under negative control by DREAM complex / pronucleus / positive regulation of dendrite development / histone H3K9me2/3 reader activity / DNA methylation-dependent constitutive heterochromatin formation / histone H3 methyltransferase activity / negative regulation of G1/S transition of mitotic cell cycle / G1 to G0 transition / synaptic transmission, GABAergic / histone methyltransferase activity / Sin3-type complex / negative regulation of gene expression, epigenetic / G1/S-Specific Transcription / spinal cord development / positive regulation of stem cell population maintenance / positive regulation of MAP kinase activity / lncRNA binding / histone deacetylase complex / negative regulation of transcription elongation by RNA polymerase II / positive regulation of protein serine/threonine kinase activity / histone methyltransferase complex / Transcriptional Regulation by E2F6 / RNA Polymerase I Transcription Initiation / G0 and Early G1 / keratinocyte differentiation / subtelomeric heterochromatin formation / positive regulation of GTPase activity / negative regulation of cell differentiation / ribonucleoprotein complex binding / positive regulation of epithelial to mesenchymal transition / Cyclin E associated events during G1/S transition / RNA polymerase II core promoter sequence-specific DNA binding / pericentric heterochromatin / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Cyclin A:Cdk2-associated events at S phase entry / Regulation of TP53 Activity through Acetylation / nucleosome binding / Chromatin modifying enzymes / heterochromatin / B cell differentiation / protein localization to chromatin / negative regulation of cytokine production involved in inflammatory response / liver regeneration / Deposition of new CENPA-containing nucleosomes at the centromere / telomere organization / Interleukin-7 signaling / negative regulation of cell migration / epigenetic regulation of gene expression / stem cell differentiation / RNA Polymerase I Promoter Opening / hippocampus development / Assembly of the ORC complex at the origin of replication / transcription corepressor binding / SUMOylation of chromatin organization proteins / Regulation of PTEN gene transcription / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / central nervous system development / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA
Similarity search - Function
: / : / AEBP2-like, C-terminal SH3 domain / : / Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain ...: / : / AEBP2-like, C-terminal SH3 domain / : / Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain / Pre-SET CXC domain / : / WD repeat binding protein EZH2 / Polycomb repressive complex 2 tri-helical domain / CXC domain / Ezh2, MCSS domain / Tesmin/TSO1-like CXC domain / Tesmin/TSO1-like CXC domain / CXC domain / Histone-lysine N-methyltransferase EZH1/2-like / CXC domain profile. / Histone-binding protein RBBP4, N-terminal / Histone-binding protein RBBP4 or subunit C of CAF1 complex / : / : / Zinc finger, C5HC2-type / C5HC2 zinc finger / ARID DNA-binding domain / ARID DNA-binding domain superfamily / ARID/BRIGHT DNA binding domain / ARID domain profile. / BRIGHT, ARID (A/T-rich interaction domain) domain / ARID/BRIGHT DNA binding domain / JmjN domain / jmjN domain / JmjN domain profile. / Small domain found in the jumonji family of transcription factors / JmjC domain, hydroxylase / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain profile. / SET domain superfamily / SET domain / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 domain / Histone-fold / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / Polycomb protein EED / Histone H3.1 / Histone-binding protein RBBP4 / Polycomb protein SUZ12 / Histone-lysine N-methyltransferase EZH2 / Zinc finger protein AEBP2 / Protein Jumonji
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsCookis, T. / Nogales, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35-GM127018 United States
National Science Foundation (NSF, United States)GM-08295 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications.
Authors: Trinity Cookis / Alexandria Lydecker / Paul Sauer / Vignesh Kasinath / Eva Nogales /
Abstract: Polycomb repressive complex 2 (PRC2) trimethylates histone H3 on K27 (H3K27me3) leading to gene silencing that is essential for embryonic development and maintenance of cell identity. PRC2 is ...Polycomb repressive complex 2 (PRC2) trimethylates histone H3 on K27 (H3K27me3) leading to gene silencing that is essential for embryonic development and maintenance of cell identity. PRC2 is regulated by protein cofactors and their crosstalk with histone modifications. Trimethylated histone H3 on K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy, we reveal that histone H3 tails containing H3K36me3 engage poorly with PRC2 and preclude its effective interaction with chromatin, while H3K4me3 binds to the allosteric site in the EED subunit, acting as an antagonist that competes with activators required for spreading of the H3K27me3 repressive mark. Thus, the location of the H3K4me3 and H3K36me3 modifications along the H3 tail allows them to target two requirements for efficient trimethylation of H3K27 by PRC2. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications.
History
DepositionJan 13, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.1Mar 5, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Polycomb protein SUZ12
L: EED
N: RBAP48
C: Isoform 2 of Histone-lysine N-methyltransferase EZH2
B: Protein Jumonji
P: Zinc finger protein AEBP2
H: DNA (26-mer)
I: H3K36me3-modified histone H3
D: DNA (26-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)353,99410
Polymers353,6099
Non-polymers3841
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 6 types, 6 molecules ALNCBP

#1: Protein Polycomb protein SUZ12 / Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor ...Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor of zeste 12 protein homolog


Mass: 72265.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SUZ12, CHET9, JJAZ1, KIAA0160 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15022
#2: Protein EED / hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic ...hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic tails 1 / WAIT-1


Mass: 50267.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75530
#3: Protein RBAP48 / Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / ...Chromatin assembly factor 1 subunit C / CAF-1 subunit C / Chromatin assembly factor I p48 subunit / CAF-I 48 kDa subunit / CAF-I p48 / Nucleosome-remodeling factor subunit RBAP48 / Retinoblastoma-binding protein 4 / RBBP-4 / Retinoblastoma-binding protein p48


Mass: 47709.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBBP4, RBAP48 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q09028
#4: Protein Isoform 2 of Histone-lysine N-methyltransferase EZH2 / ENX-1 / Enhancer of zeste homolog 2 / Lysine N-methyltransferase 6


Mass: 85492.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EZH2, KMT6 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q15910, [histone H3]-lysine27 N-trimethyltransferase
#5: Protein Protein Jumonji / Jumonji/ARID domain-containing protein 2


Mass: 49174.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JARID2, JMJ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92833
#6: Protein Zinc finger protein AEBP2 / Adipocyte enhancer-binding protein 2 / AE-binding protein 2


Mass: 31286.885 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AEBP2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6ZN18

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DNA chain , 2 types, 2 molecules HD

#7: DNA chain DNA (26-mer)


Mass: 7043.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#9: DNA chain DNA (26-MER)


Mass: 8046.153 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Protein/peptide / Non-polymers , 2 types, 2 molecules I

#10: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
#8: Protein/peptide H3K36me3-modified histone H3 / Histone H3/a / Histone H3/b / Histone H3/c / Histone H3/d / Histone H3/f / Histone H3/h / Histone ...Histone H3/a / Histone H3/b / Histone H3/c / Histone H3/d / Histone H3/f / Histone H3/h / Histone H3/i / Histone H3/j / Histone H3/k / Histone H3/l


Mass: 2322.774 Da / Num. of mol.: 1
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

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Details

Has ligand of interestN
Has protein modificationY

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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: PRC2_AJ1-450 bound to H3K36me3 modified nucleosome with tail engaged
Type: COMPLEX / Entity ID: #1-#3, #5-#9 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.9
SpecimenEmbedding 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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61193 / Symmetry type: POINT
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316413
ELECTRON MICROSCOPYf_angle_d0.61422537
ELECTRON MICROSCOPYf_dihedral_angle_d18.3612612
ELECTRON MICROSCOPYf_chiral_restr0.0432519
ELECTRON MICROSCOPYf_plane_restr0.0042743

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