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- PDB-8g57: Structure of nucleosome-bound Sirtuin 6 deacetylase -

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Basic information

Entry
Database: PDB / ID: 8g57
TitleStructure of nucleosome-bound Sirtuin 6 deacetylase
Components
  • DNA strand 1DNA
  • DNA strand 2DNA
  • Histone H2A type 1-B/E
  • Histone H2B type 1-J
  • Histone H3
  • Histone H4
  • NAD-dependent protein deacylase sirtuin-6
KeywordsTRANSFERASE/DNA / Nucleosome / Sirt6 / aging / DNA damage / repair / deacetylation / diacylation / apo / chromatin / heterochromatin / GENE REGULATION / TRANSFERASE-DNA complex
Function / homology
Function and homology information


NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / chromosome, subtelomeric region ...NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / chromosome, subtelomeric region / pericentric heterochromatin formation / NAD+-protein-arginine ADP-ribosyltransferase activity / positive regulation of protein localization to chromatin / DNA damage sensor activity / positive regulation of stem cell differentiation / positive regulation of blood vessel branching / retrotransposon silencing / NAD-dependent protein lysine deacetylase activity / protein localization to site of double-strand break / cardiac muscle cell differentiation / protein acetyllysine N-acetyltransferase / NAD-dependent histone deacetylase activity / positive regulation of chondrocyte proliferation / positive regulation of telomere maintenance / protein deacetylation / negative regulation of glucose import / TORC2 complex binding / lncRNA binding / negative regulation of glycolytic process / DNA repair-dependent chromatin remodeling / negative regulation of protein localization to chromatin / positive regulation of double-strand break repair / positive regulation of vascular endothelial cell proliferation / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / negative regulation of protein import into nucleus / positive regulation of stem cell population maintenance / positive regulation of stem cell proliferation / regulation of protein secretion / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / negative regulation of cellular senescence / subtelomeric heterochromatin formation / regulation of lipid metabolic process / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / NAD+ binding / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of fat cell differentiation / protein localization to CENP-A containing chromatin / negative regulation of gluconeogenesis / regulation of protein localization to plasma membrane / pericentric heterochromatin / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / response to UV / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Deposition of new CENPA-containing nucleosomes at the centromere / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / Meiotic synapsis / RNA Polymerase I Promoter Opening / nucleotidyltransferase activity / Assembly of the ORC complex at the origin of replication / DNA methylation / Condensation of Prophase Chromosomes / positive regulation of protein export from nucleus / HCMV Late Events / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / innate immune response in mucosa / PRC2 methylates histones and DNA / Defective pyroptosis / HDACs deacetylate histones / determination of adult lifespan / RNA Polymerase I Promoter Escape / Nonhomologous End-Joining (NHEJ) / lipopolysaccharide binding / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / base-excision repair / circadian regulation of gene expression / protein destabilization / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / NoRC negatively regulates rRNA expression / G2/M DNA damage checkpoint / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / DNA Damage/Telomere Stress Induced Senescence / positive regulation of insulin secretion / Metalloprotease DUBs / chromatin DNA binding
Similarity search - Function
Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. ...Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily / 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. / 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
DNA / DNA (> 10) / DNA (> 100) / Histone H3 / Histone H2A type 1-B/E / Histone H2B type 1-J / Histone H4 / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
Xenopus laevis (African clawed frog)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsChio, U.S. / Rechiche, O. / Bryll, A.R. / Zhu, J. / Feldman, J.L. / Peterson, C.L. / Tan, S. / Armache, J.-P.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32GM137463 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM127034 United States
National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB)T32BM107000 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM127034 United States
CitationJournal: Sci Adv / Year: 2023
Title: Cryo-EM structure of the human Sirtuin 6-nucleosome complex.
Authors: Un Seng Chio / Othman Rechiche / Alysia R Bryll / Jiang Zhu / Erik M Leith / Jessica L Feldman / Craig L Peterson / Song Tan / Jean-Paul Armache /
Abstract: Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups ...Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo-electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56.
History
DepositionFeb 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
K: NAD-dependent protein deacylase sirtuin-6
A: Histone H3
B: Histone H4
C: Histone H2A type 1-B/E
D: Histone H2B type 1-J
E: Histone H3
F: Histone H4
G: Histone H2A type 1-B/E
H: Histone H2B type 1-J
I: DNA strand 1
J: DNA strand 2


Theoretical massNumber of molelcules
Total (without water)237,40611
Polymers237,40611
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 9 molecules KAEBFCGDH

#1: Protein NAD-dependent protein deacylase sirtuin-6 / NAD-dependent protein deacetylase sirtuin-6 / Protein mono-ADP-ribosyltransferase sirtuin-6 / ...NAD-dependent protein deacetylase sirtuin-6 / Protein mono-ADP-ribosyltransferase sirtuin-6 / Regulatory protein SIR2 homolog 6 / hSIRT6 / SIR2-like protein 6


Mass: 39708.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8N6T7, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups, protein acetyllysine N-acetyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Protein Histone H3 /


Mass: 15004.579 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: LOC121398065 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A310TTQ1
#3: Protein Histone H4 /


Mass: 9704.396 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 (E. coli) / References: UniProt: P62799
#4: Protein Histone H2A type 1-B/E / Histone H2A.2 / Histone H2A/a / Histone H2A/m


Mass: 14034.355 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H2AC4, H2AFM, HIST1H2AB, H2AC8, H2AFA, HIST1H2AE / Production host: Escherichia coli (E. coli) / References: UniProt: P04908
#5: Protein Histone H2B type 1-J / Histone H2B.1 / Histone H2B.r / H2B/r


Mass: 13804.045 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC11, H2BFR, HIST1H2BJ / Production host: Escherichia coli (E. coli) / References: UniProt: P06899

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DNA chain , 2 types, 2 molecules IJ

#6: DNA chain DNA strand 1 / DNA


Mass: 46541.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#7: DNA chain DNA strand 2 / DNA


Mass: 46061.348 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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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: Sirt6 deacetylase bound to a nucleosome assembled with 172-bp 601 Widom DNA
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightValue: 300 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Details: 12.5 mM HEPES pH 7.5, 60 mM KCl, 1.5% glycerol, 1 mM DTT
Buffer component
IDConc.NameFormulaBuffer-ID
160 mMPotassium chlorideKCl1
212.5 mM2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acidHEPES1
31 mM(2S,3S)-1,4-Bis(sulfanyl)butane-2,3-diolDithiothreitol1
41.5 %Propane-1,2,3-triolGlycerol1
SpecimenConc.: 1.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: SIRT6 deacetylase bound to asymmetrical nucleosome with 172 DNA base-pairs
Specimen supportDetails: Glass slides were wrapped with fresh parafilm. Tweezers were washed with ethanol, dried, and then used to pick grids from a grid box. Grids were carefully examined and placed on the parafilm- ...Details: Glass slides were wrapped with fresh parafilm. Tweezers were washed with ethanol, dried, and then used to pick grids from a grid box. Grids were carefully examined and placed on the parafilm-covered slides. These slides were then placed into the PelCO easyGLOW glow discharger, and treated there.
Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 / Nominal magnification: 81000 X / Calibrated magnification: 81000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm / Calibrated defocus min: 1000 nm / Calibrated defocus max: 2200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 75 K / Temperature (min): 64 K
Image recordingAverage exposure time: 3.3 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 11872
Details: Data was collected in Super Resolution mode, thus the image size is 11520 (width) x 8184 (height)
EM imaging opticsEnergyfilter slit width: 20 eV / Phase plate: OTHER
Image scansSampling size: 5 µm / Width: 5760 / Height: 4092

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
1cryoSPARC3.32particle selection
2Latitudeimage acquisition
4cryoSPARC3.32CTF correction
7UCSF Chimera1.15model fitting
8Coot0.9.8model fitting
10Coot0.9.8model refinement
11PHENIX1.2model refinement
13cryoSPARC3.32final Euler assignment
14cryoSPARC3.32classification
15cryoSPARC3.323D reconstruction
CTF correctionDetails: CTF was estimated using Patch CTF estimation (multi), and was applied during the refinement
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 12821862 / Details: Particles were selected using Blob Picker
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71603 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingB value: 79 / Protocol: FLEXIBLE FIT / Space: REAL
Details: UCSF Chimera was used for manual fitting of the models; It was then used for optimizing the fit by using option Fit in Map. Then Coot was used to analyze the fits, build and adjust the ...Details: UCSF Chimera was used for manual fitting of the models; It was then used for optimizing the fit by using option Fit in Map. Then Coot was used to analyze the fits, build and adjust the models into the existing densities, and refine parts of the model. Once the model has been built, validated and adjusted, we used phenix.real_space_refine to fix and improve the fit into the densities
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeSource nameType
13LZ0

3lz0

13LZ0PDBexperimental model
23PKI

3pki

13PKIPDBexperimental model
37CL0

7cl0

17CL0PDBexperimental model

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