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

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Entry
Database: PDB / ID: 6jma
Titlecryo-EM structure of DOT1L bound to H2B ubiquitinated nucleosome
Components
  • DNA I&J
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
  • Histone-lysine N-methyltransferase, H3 lysine-79 specificHistone methyltransferase
  • Ubiquitin
KeywordsGENE REGULATION / histone / nucleosome / methylation
Function / homology
Function and homology information


APC/C:Cdc20 mediated degradation of Cyclin B / Budding and maturation of HIV virion / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Activation of NF-kappaB in B cells / ISG15 antiviral mechanism / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / ER-Phagosome pathway / Downregulation of ERBB4 signaling ...APC/C:Cdc20 mediated degradation of Cyclin B / Budding and maturation of HIV virion / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Activation of NF-kappaB in B cells / ISG15 antiviral mechanism / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / ER-Phagosome pathway / Downregulation of ERBB4 signaling / Spry regulation of FGF signaling / Downregulation of ERBB2:ERBB3 signaling / NOD1/2 Signaling Pathway / TICAM1, RIP1-mediated IKK complex recruitment / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Negative regulation of FGFR1 signaling / Autodegradation of Cdh1 by Cdh1:APC/C / SCF-beta-TrCP mediated degradation of Emi1 / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Membrane binding and targetting of GAG proteins / Assembly Of The HIV Virion / APC-Cdc20 mediated degradation of Nek2A / Translesion synthesis by REV1 / Vif-mediated degradation of APOBEC3G / Vpu mediated degradation of CD4 / EGFR downregulation / Degradation of AXIN / Autodegradation of the E3 ubiquitin ligase COP1 / Deactivation of the beta-catenin transactivating complex / Myoclonic epilepsy of Lafora / ABC-family proteins mediated transport / Circadian Clock / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / activated TAK1 mediates p38 MAPK activation / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / AUF1 (hnRNP D0) binds and destabilizes mRNA / Asymmetric localization of PCP proteins / Degradation of DVL / PKMTs methylate histone lysines / Regulation of FZD by ubiquitination / Pink/Parkin Mediated Mitophagy / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of TNFR1 signaling / TNFR1-induced NFkappaB signaling pathway / Hedgehog ligand biogenesis / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Dectin-1 mediated noncanonical NF-kB signaling / CLEC7A (Dectin-1) signaling / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / Glycogen synthesis / Regulation of innate immune responses to cytosolic DNA / SCF(Skp2)-mediated degradation of p27/p21 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Degradation of beta-catenin by the destruction complex / TCF dependent signaling in response to WNT / Downstream TCR signaling / NRIF signals cell death from the nucleus / p75NTR recruits signalling complexes / NF-kB is activated and signals survival / Regulation of activated PAK-2p34 by proteasome mediated degradation / NOTCH1 Intracellular Domain Regulates Transcription / Activated NOTCH1 Transmits Signal to the Nucleus / Downregulation of TGF-beta receptor signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / NOTCH2 Activation and Transmission of Signal to the Nucleus / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Separation of Sister Chromatids / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Regulation of PLK1 Activity at G2/M Transition / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Stimuli-sensing channels / Constitutive Signaling by NOTCH1 HD Domain Mutants / FCERI mediated NF-kB activation / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Hedgehog 'on' state / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Regulation of RUNX2 expression and activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / InlA-mediated entry of Listeria monocytogenes into host cells / InlB-mediated entry of Listeria monocytogenes into host cell / E3 ubiquitin ligases ubiquitinate target proteins / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Downregulation of ERBB2 signaling / Clathrin-mediated endocytosis / Cargo recognition for clathrin-mediated endocytosis / The role of GTSE1 in G2/M progression after G2 checkpoint / Regulation of PTEN localization / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Stabilization of p53 / G2/M Checkpoints / Cyclin D associated events in G1 / rt:r-hsa-69229: / CDK-mediated phosphorylation and removal of Cdc6 / Orc1 removal from chromatin
Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / Ubiquitin domain profile. / CENP-T/Histone H4, histone fold / Ubiquitin conserved site / Ubiquitin / Polyketide synthase, enoylreductase domain / Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / S-adenosyl-L-methionine-dependent methyltransferase / Ubiquitin-like domain superfamily ...Histone-lysine N-methyltransferase DOT1 (EC 2.1.1.43) domain profile. / Ubiquitin domain profile. / CENP-T/Histone H4, histone fold / Ubiquitin conserved site / Ubiquitin / Polyketide synthase, enoylreductase domain / Histone H3-K79 methyltransferase, metazoa / Histone-lysine N-methyltransferase DOT1 domain / S-adenosyl-L-methionine-dependent methyltransferase / Ubiquitin-like domain superfamily / Histone H3-K79 methyltransferase / Histone H2A, C-terminal domain / Histone H2A conserved site / NAD(P)-binding domain superfamily / Histone H2B signature. / Zinc-binding dehydrogenase / Core histone H2A/H2B/H3/H4 / Ubiquitin family / Histone methylation protein DOT1 / Alcohol dehydrogenase GroES-like domain / Centromere kinetochore component CENP-T histone fold / C-terminus of histone H2A / Histone H2A signature. / Histone H4 signature. / Zinc-containing alcohol dehydrogenases signature. / Ubiquitin domain signature. / Alcohol dehydrogenase, N-terminal / Histone H4, conserved site / Alcohol dehydrogenase, C-terminal / GroES-like superfamily / Histone H2B / Ubiquitin domain / Histone H4 / Histone H2A / Alcohol dehydrogenase, zinc-type, conserved site / TATA box binding protein associated factor (TAF) / Histone H2A/H2B/H3 / Histone-fold
Histone H2B 1.1 / Polyubiquitin-B / Histone H4 / Nerol dehydrogenase / Histone H2A / Histone-lysine N-methyltransferase, H3 lysine-79 specific
Specimen sourcesynthetic construct (others)
Xenopus laevis (African clawed frog)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.8 Å
AuthorsJang, S. / Song, J.J.
Funding supportKorea, Republic Of , 3件
OrganizationGrant numberCountry
National Research Foundation (Korea)NRF-2016R1A2B3006293Korea, Republic Of
National Research Foundation (Korea)NRF-2016K1A1A2912057Korea, Republic Of
National Research Foundation (Korea)NRF- 2016H1A2A1908806Korea, 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.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Mar 7, 2019 / Release: May 15, 2019
RevisionDateData content typeGroupCategoryItemProviderType
1.0May 15, 2019Structure modelrepositoryInitial release
1.1May 22, 2019Structure modelData collection / Database referencescitation / citation_author_citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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Assembly

Deposited unit
I: DNA I&J
J: DNA I&J
A: Histone H3.2
B: Histone H4
C: Histone H2A
D: Histone H2B 1.1
E: Histone H3.2
F: Histone H4
G: Histone H2A
H: Histone H2B 1.1
X: Histone-lysine N-methyltransferase, H3 lysine-79 specific
Y: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)206,47813
Polymers206,08012
Non-polymers3981
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area54510 Å2
ΔGint-367 kcal/mol
Surface area81990 Å2

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Components

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Protein/peptide , 6 types, 10 molecules AEBFCGDHXY

#2: Protein/peptide Histone H3.2


Mass: 11488.410 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21 / References: UniProt: P84233
#3: Protein/peptide Histone H4 /


Mass: 9990.770 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21 / References: UniProt: P62799
#4: Protein/peptide Histone H2A /


Mass: 12660.719 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: hist1h2aj / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21 / References: UniProt: Q6AZJ8
#5: Protein/peptide Histone H2B 1.1 / H2B1.1


Mass: 10478.032 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21 / References: UniProt: P02281
#6: Protein/peptide Histone-lysine N-methyltransferase, H3 lysine-79 specific / Histone methyltransferase / DOT1-like protein


Mass: 37930.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOT1L / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21
References: UniProt: Q8TEK3, histone-lysine N-methyltransferase
#7: Protein/peptide Ubiquitin /


Mass: 8576.831 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): BL21 / References: UniProt: P0CG47

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DNA chain / Non-polymers , 2 types, 3 molecules IJ

#1: DNA chain DNA I&J


Mass: 35168.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli DH5[alpha] (bacteria)
#8: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


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

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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: DOT1L bound to H2B ubiquitinated nucleosome / Type: COMPLEX / Entity ID: 1, 2, 3, 4, 5, 6, 7 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.29 MDa / Experimental value: NO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 37.28 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 122242 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT

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