Correction to The 2.5 Å Crystal Structure of the SIRT1 Catalytic Domain Bound to Nicotinamide Adenine Dinucleotide (NAD⁺) and an Indole (EX527 Analogue) Reveals a Novel Mechanism of Histone Deacetylase Inhibition

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

“…This makes the indole compound more specific to SIRT1, as discussed in studies by Napper et al Along with the Sir2Tm complex structures, the analysis of product formation suggests that Ex-243 inhibits the enzyme by stabilizing a sirtuin complex with the coproduct (Gertz et al, 2013). A crystal structure of SIRT1-NAD + in complex with CHIC35 (PDB:4I5I, Table 2; Figure 8B; Zhao et al, 2016), an analogue of SIRT1 inhibitor selisistat, has defined a novel mechanism of deacetylation inhibition. Compound CHIC35 and NAD + bind cooperatively and the inhibitor binding forces the extended NAD + conformation which inhibits the substrate binding.…”

“…However, at present, SIRT1 is the more extensively studied isoform. Structural characterizations of a deleted SIRT1 construct have shed light on the modulator binding and key regulatory elements (Davenport et al, 2014;Cao et al, 2015;Dai et al, 2015;Zhao et al, 2016). There are more structures available for HDAC inhibitor complexes than SIRT1 activator complexes.…”

“…Full-length SIRT1 consists of three major regions; the N-terminal domain (NTD) with three helices (183-229), the HDAC domain (229-516), and a β-hairpin from the C-terminal regulatory segment (CTR), which is also known as the region essential for SIRT1 activity (ESA) (Figures 5A,B, Blue colored) (Cao et al, 2015;Vaquero et al, 2004;Zhao et al, 2016). The NTD are also called sirtuin-activating compound (STACs) binding domains (SBD) (Figures 5A,B, yellow-colored).…”

“…Advancing current understanding of the distinct modes of SIRT1 and SIRT2 catalytic activity has become extremely challenging since there are no specific inhibitors that target only the protein of interest without influencing other family members. Structural information on sirtuin inhibition is still insufficient and there are very few reports on structures of sirtuins in complex with inhibitors (Nguyen et al, 2013b;Disch et al, 2013;Gertz et al, 2013;Rumpf et al, 2015a;Rumpf et al, 2015b;Zhao et al, 2016; Figure 7C).…”

“…However, severe neurotoxicity and other systemic side effects are severe disadvantages to its use in treatment (Peltier and Russell, 2002). The indole derivatives have been widely studied for the catalytic inhibition of SIRT1 protein (Huber et al, 2010;Manjula et al, 2019;Napper et al, 2007;Panathur et al, 2015;Zhao et al, 2016). In the study on the indole derivative, selisistat provided the NAD + inhibition mechanism of catalysis (Gertz et al, 2013).…”