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- EMDB-9844: cryo-EM structure of DOT1L bound to H2B ubiquitinated nucleosome -

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Basic information

Entry
Database: EMDB / ID: EMD-9844
Titlecryo-EM structure of DOT1L bound to H2B ubiquitinated nucleosome
Map datacatalytic domain of DOT1L bound to H2B ubiquitinated nucleosome.
Sample
  • Complex: DOT1L bound to H2B ubiquitinated nucleosome
    • DNA: DNA I&J
    • Protein or peptide: Histone H3.2
    • Protein or peptide: Histone H4
    • Protein or peptide: Histone H2A
    • Protein or peptide: Histone H2B 1.1
    • Protein or peptide: Histone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
    • Protein or peptide: Ubiquitin
  • Ligand: S-ADENOSYLMETHIONINES-Adenosyl methionine
Keywordshistone / nucleosome / methylation / GENE REGULATION
Function / homology
Function and homology information


: / histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / regulation of receptor signaling pathway via JAK-STAT / histone H3 methyltransferase activity / positive regulation of protein monoubiquitination ...: / histone H3K79 trimethyltransferase activity / [histone H3]-lysine79 N-trimethyltransferase / histone H3K79 methyltransferase activity / regulation of transcription regulatory region DNA binding / hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / regulation of receptor signaling pathway via JAK-STAT / histone H3 methyltransferase activity / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / fat pad development / female gonad development / histone methyltransferase activity / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / regulation of proteasomal protein catabolic process / heterochromatin formation / energy homeostasis / regulation of neuron apoptotic process / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Constitutive Signaling by NOTCH1 HD Domain Mutants / Endosomal Sorting Complex Required For Transport (ESCRT) / NOTCH2 Activation and Transmission of Signal to the Nucleus / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / telomere organization / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / Translesion synthesis by REV1 / NF-kB is activated and signals survival / Regulation of PTEN localization / Translesion synthesis by POLK / Regulation of BACH1 activity / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Regulation of activated PAK-2p34 by proteasome mediated degradation / InlB-mediated entry of Listeria monocytogenes into host cell / IKK complex recruitment mediated by RIP1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / neuron projection morphogenesis / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / regulation of mitochondrial membrane potential / Autodegradation of Cdh1 by Cdh1:APC/C / TNFR1-induced NF-kappa-B signaling pathway / DNA damage checkpoint signaling / APC/C:Cdc20 mediated degradation of Securin / positive regulation of protein ubiquitination / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / SCF-beta-TrCP mediated degradation of Emi1 / Regulation of NF-kappa B signaling / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus / activated TAK1 mediates p38 MAPK activation / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / Deactivation of the beta-catenin transactivating complex / Degradation of DVL / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Recognition of DNA damage by PCNA-containing replication complex
Similarity search - Function
Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. ...Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / Histone H3-K79 methyltransferase / Histone methylation protein DOT1 / Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / 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 H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H3 signature 1. / Ubiquitin conserved site / Ubiquitin domain / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Ubiquitin domain signature. / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Histone H2B 1.1 / Polyubiquitin-B / Histone H4 / Histone H3.2 / Histone H2A / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog) / synthetic construct (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsJang S / Song JJ
Funding support Korea, Republic Of, 3 items
OrganizationGrant numberCountry
National Research Foundation (Korea)NRF-2016R1A2B3006293 Korea, Republic Of
National Research Foundation (Korea)NRF-2016K1A1A2912057 Korea, Republic Of
National Research Foundation (Korea)NRF- 2016H1A2A1908806 Korea, Republic Of
CitationJournal: Genes Dev / Year: 2019
Title: Structural basis of recognition and destabilization of the histone H2B ubiquitinated nucleosome by the DOT1L histone H3 Lys79 methyltransferase.
Authors: Seongmin Jang / Chanshin Kang / Han-Sol Yang / Taeyang Jung / Hans Hebert / Ka Young Chung / Seung Joong Kim / Sungchul Hohng / Ji-Joon Song /
Abstract: DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we ...DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we present cryo-EM structures of DOT1L complexes with unmodified or H2B ubiquitinated nucleosomes, showing that DOT1L recognizes H2B ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L, respectively. Furthermore, the structures combined with single-molecule FRET experiments show that H2B ubiquitination enhances a noncatalytic function of the DOT1L-destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.
History
DepositionMar 7, 2019-
Header (metadata) releaseMay 15, 2019-
Map releaseMay 15, 2019-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0251
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.0251
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6jma
  • Surface level: 0.0251
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9844.png

Downloads & links

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Map

FileDownload / File: emd_9844.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcatalytic domain of DOT1L bound to H2B ubiquitinated nucleosome.
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.0251 / Movie #1: 0.0251
Minimum - Maximum-0.056371503 - 0.1053533
Average (Standard dev.)0.0010058607 (±0.0055386866)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 233.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z233.200233.200233.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ208208208
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-0.0560.1050.001

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Supplemental data

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Sample components

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Entire : DOT1L bound to H2B ubiquitinated nucleosome

EntireName: DOT1L bound to H2B ubiquitinated nucleosome
Components
  • Complex: DOT1L bound to H2B ubiquitinated nucleosome
    • DNA: DNA I&J
    • Protein or peptide: Histone H3.2
    • Protein or peptide: Histone H4
    • Protein or peptide: Histone H2A
    • Protein or peptide: Histone H2B 1.1
    • Protein or peptide: Histone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
    • Protein or peptide: Ubiquitin
  • Ligand: S-ADENOSYLMETHIONINES-Adenosyl methionine

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Supramolecule #1: DOT1L bound to H2B ubiquitinated nucleosome

SupramoleculeName: DOT1L bound to H2B ubiquitinated nucleosome / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 290 KDa

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Macromolecule #1: DNA I&J

MacromoleculeName: DNA I&J / type: dna / ID: 1 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 35.168547 KDa
SequenceString: (DA)(DG)(DA)(DT)(DT)(DC)(DT)(DA)(DC)(DC) (DA)(DA)(DA)(DA)(DG)(DT)(DG)(DT)(DA)(DT) (DT)(DT)(DG)(DG)(DA)(DA)(DA)(DC)(DT) (DG)(DC)(DT)(DC)(DC)(DA)(DT)(DC)(DA)(DA) (DA) (DA)(DG)(DG)(DC)(DA)(DT) ...String:
(DA)(DG)(DA)(DT)(DT)(DC)(DT)(DA)(DC)(DC) (DA)(DA)(DA)(DA)(DG)(DT)(DG)(DT)(DA)(DT) (DT)(DT)(DG)(DG)(DA)(DA)(DA)(DC)(DT) (DG)(DC)(DT)(DC)(DC)(DA)(DT)(DC)(DA)(DA) (DA) (DA)(DG)(DG)(DC)(DA)(DT)(DG)(DT) (DT)(DC)(DA)(DG)(DC)(DT)(DG)(DA)(DA)(DT) (DT)(DC) (DA)(DG)(DC)(DT)(DG)(DA)(DA) (DC)(DA)(DT)(DG)(DC)(DC)(DT)(DT)(DT)(DT) (DG)(DA)(DT) (DG)(DG)(DA)(DG)(DC)(DA) (DG)(DT)(DT)(DT)(DC)(DC)(DA)(DA)(DA)(DT) (DA)(DC)(DA)(DC) (DT)(DT)(DT)(DT)(DG) (DG)(DT)(DA)(DG)(DA)(DA)(DT)(DC)(DT)

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Macromolecule #2: Histone H3.2

MacromoleculeName: Histone H3.2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 11.48841 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
PHRYRPGTVA LREIRRYQKS TELLIRKLPF QRLVREIAQD FKTDLRFQSS AVMALQEASE AYLVGLFEDT NLCAIHAKRV TIMPKDIQL ARRIRGERA

UniProtKB: Histone H3.2

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Macromolecule #3: Histone H4

MacromoleculeName: Histone H4 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 9.99077 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
KRHRKVLRDN IQGITKPAIR RLARRGGVKR ISGLIYEETR GVLKVFLENV IRDAVTYTEH AKRKTVTAMD VVYALKRQGR TLYGFGG

UniProtKB: Histone H4

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Macromolecule #4: Histone H2A

MacromoleculeName: Histone H2A / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 12.660719 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
AKTRSSRAGL QFPVGRVHRL LRKGNYAERV GAGAPVYLAA VLEYLTAEIL ELAGNAARDN KKTRIIPRHL QLAVRNDEEL NKLLGRVTI AQGGVLPNIQ SVLLPKKTES SKSAKSK

UniProtKB: Histone H2A

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Macromolecule #5: Histone H2B 1.1

MacromoleculeName: Histone H2B 1.1 / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 10.478032 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
TRKESYAIYV YKVLKQVHPD TGISSKAMSI MNSFVNDVFE RIAGEASRLA HYNKRSTITS REIQTAVRLL LPGELAKHAV SEGTKAVTK YTSAK

UniProtKB: Histone H2B 1.1

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Macromolecule #6: Histone-lysine N-methyltransferase, H3 lysine-79 specific

MacromoleculeName: Histone-lysine N-methyltransferase, H3 lysine-79 specific
type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO / EC number: histone-lysine N-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.930039 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: LELRLKSPVG AEPAVYPWPL PVYDKHHDAA HEIIETIRWV CEEIPDLKLA MENYVLIDYD TKSFESMQRL CDKYNRAIDS IHQLWKGTT QPMKLNTRPS TGLLRHILQQ VYNHSVTDPE KLNNYEPFSP EVYGETSFDL VAQMIDEIKM TDDDLFVDLG S GVGQVVLQ ...String:
LELRLKSPVG AEPAVYPWPL PVYDKHHDAA HEIIETIRWV CEEIPDLKLA MENYVLIDYD TKSFESMQRL CDKYNRAIDS IHQLWKGTT QPMKLNTRPS TGLLRHILQQ VYNHSVTDPE KLNNYEPFSP EVYGETSFDL VAQMIDEIKM TDDDLFVDLG S GVGQVVLQ VAAATNCKHH YGVEKADIPA KYAETMDREF RKWMKWYGKK HAEYTLERGD FLSEEWRERI ANTSVIFVNN FA FGPEVDH QLKERFANMK EGGRIVSSKP FAPLNFRINS RNLSDIGTIM RVVELSPLKG SVSWTGKPVS YYLHTIDRTI LEN YFSSLK NP

UniProtKB: Histone-lysine N-methyltransferase, H3 lysine-79 specific

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Macromolecule #7: Ubiquitin

MacromoleculeName: Ubiquitin / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.576831 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString:
MQIFVKTLTG KTITLEVEPS DTIENVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKESTLHLV LRLRGG

UniProtKB: Polyubiquitin-B

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Macromolecule #8: S-ADENOSYLMETHIONINE

MacromoleculeName: S-ADENOSYLMETHIONINE / type: ligand / ID: 8 / Number of copies: 1 / Formula: SAM
Molecular weightTheoretical: 398.437 Da
Chemical component information

ChemComp-SAM:
S-ADENOSYLMETHIONINE / S-Adenosyl methionine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 37.28 e/Å2

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 122242
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

PDB-6jma:
cryo-EM structure of DOT1L bound to H2B ubiquitinated nucleosome

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