9VH0

SIRT2-H187A structure in complex with H3K18myr peptide and native NAD

Summary for 9VH0

• Entry DOI: 10.2210/pdb9vh0/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, Histone H3.1, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: deacylated, cell cycle regulation, metabolic regulation, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 71729.14

Authors

Zhang, N.,Hao, Q. (deposition date: 2025-06-16, release date: 2025-09-24, Last modification date: 2025-11-12)

Primary citation

Zhang, N.,Pow, K.C.,Chen, L.,Hao, Q.
Structural basis of SIRT2 pre-catalysis NAD + binding dynamics and mechanism.
Rsc Chem Biol, 6:1749-1758, 2025

PubMed Abstract: Sirtuins are an evolutionarily conserved family of NAD-dependent deacylases whose catalytic mechanism remains under active investigation. While previous studies have captured sirtuin reaction intermediates using thioacetyl-lysine analogs, here we report six crystal structures of human SIRT2 in complex with native myristoylated peptides and NAD, revealing the sequence of changes from initial NAD binding to the formation of intermediate I. Our structures provide direct structural evidence for: (1) zinc-binding domain shift during NAD entry, (2) water-mediated hydrogen-bond formation that disrupts nicotinamide aromaticity preceding cleavage, and (3) the formation of intermediate I. Additionally, we determined the structures of two functionally critical mutants (SIRT2 and SIRT2), demonstrating their roles in stabilizing NAD in a productive conformation. These findings complete the comprehensive structural framework for the sirtuin deacylation mechanism and highlight key residues governing catalytic efficiency.

PubMed: 40963517
DOI: 10.1039/d5cb00169b

Experimental method

X-RAY DIFFRACTION (2.41 Å)