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TitleStructural and enzymatic plasticity of SIRT6 deacylase activity.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 5, Page 108446, Year 2025
Publish dateMar 25, 2025
AuthorsZhipeng 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 /
PubMed AbstractSirtuin 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.
External linksJ Biol Chem / PubMed:40147774 / PubMed Central
MethodsEM (single particle)
Resolution3.2 Å
Structure data

EMDB-48086, PDB-9eil:
SIRT6 bound to an H3K27Ac nucleosome
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

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)

ChemComp-ZN:
Unknown entry

Source
  • xenopus laevis (African clawed frog)
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsGENE REGULATION / nucleosome / SIRTUIN6 / histone deacylation / H3K27Ac

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