9EIL

SIRT6 bound to an H3K27Ac nucleosome

Summary for 9EIL

• Entry DOI: 10.2210/pdb9eil/pdb
• EMDB information: 48086
• Descriptor: Histone H3.2, Histone H4, Histone H2A type 1, ... (9 entities in total)
• Functional Keywords: nucleosome, sirtuin6, histone deacylation, h3k27ac, gene regulation
• Biological source: Xenopus laevis (African clawed frog); More
• Total number of polymer chains: 11
• Total formula weight: 262113.59

Authors

Markert, J.,Wang, Z.,Cole, P.,Farnung, L. (deposition date: 2024-11-26, release date: 2025-07-09)

Primary citation

Wang, Z.A.,Markert, J.,Whedon, S.D.,Abeywardana, M.Y.,Sheng, X.,Nam, E.,Lee, K.,Chen, M.,Waterbury, A.,Zhao, Y.,Farnung, L.,Cole, P.A.
Structural and enzymatic plasticity of SIRT6 deacylase activity.
J.Biol.Chem., 301:108446-108446, 2025

PubMed 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 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.

PubMed: 40147774
DOI: 10.1016/j.jbc.2025.108446

Experimental method

ELECTRON MICROSCOPY (3.2 Å)