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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 1
  • DNA strand 2
  • 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


histone H3K56 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K9 deacetylase activity, hydrolytic mechanism / histone H3K9 deacetylase activity, NAD-dependent / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / regulation of lipid catabolic process / positive regulation of protein localization to chromatin ...histone H3K56 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / ketone biosynthetic process / histone H3K9 deacetylase activity, hydrolytic mechanism / histone H3K9 deacetylase activity, NAD-dependent / protein delipidation / NAD+-protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / regulation of lipid catabolic process / positive regulation of protein localization to chromatin / NAD+-protein-arginine ADP-ribosyltransferase activity / DNA damage sensor activity / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / positive regulation of stem cell differentiation / negative regulation of D-glucose import / positive regulation of chondrocyte proliferation / transposable element silencing / cardiac muscle cell differentiation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / pericentric heterochromatin formation / protein deacetylation / histone deacetylase activity, NAD-dependent / protein localization to site of double-strand break / positive regulation of blood vessel branching / negative regulation of glycolytic process / TORC2 complex binding / negative regulation of protein localization to chromatin / positive regulation of vascular endothelial cell proliferation / histone deacetylase regulator activity / negative regulation of protein import into nucleus / regulation of double-strand break repair via homologous recombination / regulation of protein secretion / positive regulation of double-strand break repair / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / lncRNA binding / negative regulation of gene expression, epigenetic / NAD+-protein mono-ADP-ribosyltransferase activity / positive regulation of stem cell population maintenance / positive regulation of telomere maintenance / regulation of lipid metabolic process / negative regulation of cellular senescence / site of DNA damage / Transferases; Glycosyltransferases; Pentosyltransferases / negative regulation of transcription elongation by RNA polymerase II / NAD+ poly-ADP-ribosyltransferase activity / NAD+ binding / negative regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of gluconeogenesis / positive regulation of fat cell differentiation / subtelomeric heterochromatin formation / pericentric heterochromatin / response to UV / regulation of protein localization to plasma membrane / protein localization to CENP-A containing chromatin / nucleosome binding / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / enzyme regulator activity / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / nucleotidyltransferase activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / RNA Polymerase I Promoter Opening / Inhibition of DNA recombination at telomere / Meiotic synapsis / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / DNA methylation / positive regulation of protein export from nucleus / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / SIRT1 negatively regulates rRNA expression / HCMV Late Events / innate immune response in mucosa / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / determination of adult lifespan / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / circadian regulation of gene expression / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / lipopolysaccharide binding / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / base-excision repair / positive regulation of insulin secretion / regulation of circadian rhythm / G2/M DNA damage checkpoint
Similarity search - Function
Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / Histone, subunit A / Histone, subunit A / DHS-like NAD/FAD-binding domain superfamily / : / Histone H2B signature. ...Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / Histone, subunit A / Histone, subunit A / DHS-like NAD/FAD-binding domain superfamily / : / Histone H2B signature. / Histone H2A conserved site / Histone H2A signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / 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 / Orthogonal Bundle / Mainly Alpha
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
Revision 1.1Jun 19, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / em_3d_fitting_list
Item: _em_3d_fitting_list.initial_refinement_model_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
Water00
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


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


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 FIELD / 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 codeInitial refinement model-IDSource nameType
13LZ0

3lz0

13LZ01PDBexperimental model
23PKI

3pki

13PKI2PDBexperimental model
37CL0

7cl0

17CL03PDBexperimental model

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