30KE
Crystal structure of human SIRT2 in complex with KMyrMe peptide and NAD+
Summary for 30KE
| Entry DOI | 10.2210/pdb30ke/pdb |
| Descriptor | NAD-dependent protein deacetylase sirtuin-2, KMyrMe peptide, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (6 entities in total) |
| Functional Keywords | sirtuin 2, n-myristoyl-n-methyl, lysine modification, deacylase, ternary complex, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 36108.75 |
| Authors | Friedrich, F.,Einsle, O.,Jung, M.,Schiene-Fischer, C.,Schutkowski, M. (deposition date: 2026-04-30, release date: 2026-09-30, Last modification date: 2026-11-04) |
| Primary citation | Hilscher, S.,Bottcher, P.H.,Friedrich, F.,Pannek, M.,Baselious, F.,Meleshin, M.,Einsle, O.,Barinka, C.,Steegborn, C.,Sippl, W.,Jung, M.,Schutkowski, M.,Schiene-Fischer, C. Structural and Enzymatic Basis for Impaired Deacylation of N-Acyl-N-Methyl Lysine Residues. Biochemistry, 65:3092-3105, 2026 Cited by PubMed Abstract: Posttranslational lysine acetylation and methylation are generally considered mutually exclusive modifications of the ε-amino group. The recent discovery of N-acetyl-N-methyl lysine (KAcMe) on histone H4 showed that both marks can coexist on the same lysine side chain, raising the question of whether this dual modification is enzymatically reversible. Here, we synthesized model peptides containing N-acyl lysine or N-acyl-N-methyl lysine residues and tested their processing by Zn2+-dependent HDACs and NAD+-dependent sirtuins. While the corresponding unmethylated substrates were deacylated by the expected enzymes, KAcMe-containing peptides were not detectably deacetylated by either enzyme family. N-methylation also blocked HDAC8/11-mediated demyristoylation and SIRT5-mediated desuccinylation, whereas SIRT2 and SIRT6 retained weak demyristoylase activity toward N-myristoyl-N-methyl lysine. X-ray crystal structures of sirtuin-peptide complexes, supported by inhibition studies and molecular docking, reveal that N-methylation disrupts productive substrate positioning and misaligns the scissile amide bond for catalysis. These findings suggest that KAcMe is resistant to canonical lysine deacetylases and may represent a persistent chromatin-associated modification. PubMed: 42917127DOI: 10.1021/acs.biochem.6c00508 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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