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- PDB-9eil: SIRT6 bound to an H3K27Ac nucleosome -

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Basic information

Entry
Database: PDB / ID: 9eil
TitleSIRT6 bound to an H3K27Ac nucleosome
Components
  • (DNA (185-MER)) x 2
  • Histone H2A type 1
  • Histone H2B
  • Histone H3.2
  • Histone H4
  • NAD-dependent protein deacylase sirtuin-6
KeywordsGENE REGULATION / nucleosome / SIRTUIN6 / histone deacylation / H3K27Ac
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 / regulation of lipid catabolic process / chromosome, subtelomeric region / 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 / regulation of lipid catabolic process / chromosome, subtelomeric region / 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 / NAD-dependent protein lysine deacetylase activity / transposable element silencing / cardiac muscle cell differentiation / 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 / negative regulation of protein localization to chromatin / TORC2 complex binding / positive regulation of vascular endothelial cell proliferation / histone deacetylase regulator activity / regulation of double-strand break repair via homologous recombination / positive regulation of double-strand break repair / negative regulation of protein import into nucleus / regulation of protein secretion / lncRNA binding / negative regulation of gene expression, epigenetic / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / positive regulation of stem cell population maintenance / NAD+-protein mono-ADP-ribosyltransferase activity / positive regulation of telomere maintenance / pericentric heterochromatin / site of DNA damage / regulation of lipid metabolic process / NAD+ poly-ADP-ribosyltransferase activity / negative regulation of transcription elongation by RNA polymerase II / negative regulation of cellular senescence / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ binding / positive regulation of fat cell differentiation / negative regulation of gluconeogenesis / subtelomeric heterochromatin formation / regulation of protein localization to plasma membrane / response to UV / nucleosome binding / enzyme regulator activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / nucleotidyltransferase activity / positive regulation of protein export from nucleus / determination of adult lifespan / circadian regulation of gene expression / chromatin DNA binding / regulation of circadian rhythm / protein destabilization / base-excision repair / positive regulation of insulin secretion / Pre-NOTCH Transcription and Translation / positive regulation of fibroblast proliferation / protein import into nucleus / structural constituent of chromatin / transcription corepressor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / glucose homeostasis / nucleosome / site of double-strand break / heterochromatin formation / double-strand break repair / nucleosome assembly / Processing of DNA double-strand break ends / positive regulation of cold-induced thermogenesis / damaged DNA binding / chromatin remodeling / protein heterodimerization activity / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / chromatin binding / chromatin / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / DNA binding / zinc ion binding / nucleoplasm / nucleus
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 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 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 / Histone-fold
Similarity search - Domain/homology
Chem-ZSL / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H3.2 / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMarkert, J. / Wang, Z. / Cole, P. / Farnung, L.
Funding support United States, 4items
OrganizationGrant numberCountry
Richard and Susan Smith Family Foundation United States
Damon Runyon Cancer Research Foundation United States
Rita Allen Foundation United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS) United States
CitationJournal: J Biol Chem / Year: 2025
Title: Structural and enzymatic plasticity of SIRT6 deacylase activity.
Authors: Zhipeng A Wang / Jonathan Markert / Samuel D Whedon / Maheeshi Yapa Abeywardana / Xinlei Sheng / Eunju Nam / Kwangwoon Lee / Maggie Chen / Amanda Waterbury / Yingming Zhao / Lucas Farnung / Philip A Cole /
Abstract: Sirtuin 6 (SIRT6) is an NAD-dependent protein deacylase that targets lysine residues in histones in the cell nucleus, where it helps maintain genome stability and links metabolism to epigenetic ...Sirtuin 6 (SIRT6) is an NAD-dependent protein deacylase that targets lysine residues in histones in the cell nucleus, where it helps maintain genome stability and links metabolism to epigenetic control. Dysregulation of SIRT6 is believed to be associated with aging and cancer, making it of pharmacological interest. In this study, we use cryo-EM and enzymology to explore SIRT6 preference and adaptability toward different nucleosomal substrates. We have visualized a trapped complex of SIRT6 in the process of deacylating H3K27, demonstrating how SIRT6 undergoes conformational changes to remove differently positioned histone marks. Additional biochemical studies further reveal the plasticity of SIRT6, which accommodates various metabolism-linked modifications, such as lysine lactylation and β-hydroxybutyrylation. To further understand the basis for substrate selectivity of SIRT6, we explore the effects of an established G60A enzyme mutation, proximal H3 modifications, and small-molecule modulators. These findings highlight the versatility of SIRT6 and provide key mechanistic insights into its molecular recognition.
History
DepositionNov 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone H3.2
B: Histone H4
C: Histone H2A type 1
D: Histone H2B
E: Histone H3.2
F: Histone H4
G: Histone H2A type 1
H: Histone H2B
I: DNA (185-MER)
J: DNA (185-MER)
K: NAD-dependent protein deacylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)262,11413
Polymers261,46111
Non-polymers6532
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 9 molecules AEBFCGDHK

#1: Protein Histone H3.2


Mass: 15271.863 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: P84233
#2: Protein Histone H4


Mass: 11263.231 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
#3: Protein Histone H2A type 1


Mass: 13978.241 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: P06897
#4: Protein Histone H2B / H2B1.1


Mass: 13524.752 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: P02281
#7: 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: 39152.863 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

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (185-MER)


Mass: 57400.559 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (185-MER)


Mass: 56831.191 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 2 molecules

#8: Chemical ChemComp-ZSL / [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl [(3aR,5R,6R,6aR)-6-hydroxytetrahydro-2H-furo[2,3-d][1,3]oxathiol-5-yl]methyl dihydrogen diphosphate (non-preferred name)


Mass: 587.392 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C16H23N5O13P2S / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestY
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: SIRT6 bound to H3K27Ac / Type: COMPLEX / Entity ID: #1-#7 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 50.45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 124274 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00414899
ELECTRON MICROSCOPYf_angle_d0.63321348
ELECTRON MICROSCOPYf_dihedral_angle_d25.6526037
ELECTRON MICROSCOPYf_chiral_restr0.0562431
ELECTRON MICROSCOPYf_plane_restr0.0051730

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