5Y0Z

Human SIRT2 in complex with a specific inhibitor, NPD11033

Summary for 5Y0Z

• Entry DOI: 10.2210/pdb5y0z/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, (1~{R},9~{S})-11-[(2~{R})-3-[2,4-bis(2-methylbutan-2-yl)phenoxy]-2-oxidanyl-propyl]-7,11-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4-dien-6-one, ... (4 entities in total)
• Functional Keywords: sirtuin, sirt, nad-dependent deacetylase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 67494.63

Authors

Kudo, N.,Ito, A.,Yoshida, M. (deposition date: 2017-07-19, release date: 2018-07-25, Last modification date: 2023-11-22)

Primary citation

Kudo, N.,Ito, A.,Arata, M.,Nakata, A.,Yoshida, M.
Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.
Philos. Trans. R. Soc. Lond., B, Biol. Sci., 373:-, 2018

PubMed Abstract: SIRT2 is a member of the human sirtuin family of proteins and possesses NAD-dependent lysine deacetylase/deacylase activity. SIRT2 has been implicated in carcinogenesis in various cancers including leukaemia and is considered an attractive target for cancer therapy. Here, we identified NPD11033, a selective small-molecule SIRT2 inhibitor, by a high-throughput screen using the RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins and zinc-dependent deacetylases. Crystallographic analysis revealed a unique mode of action, in which NPD11033 creates a hydrophobic cavity behind the substrate-binding pocket after a conformational change of the Zn-binding small domain of SIRT2. Furthermore, it forms a hydrogen bond to the active site histidine residue. In addition, NPD11033 inhibited cell growth of human pancreatic cancer PANC-1 cells with a concomitant increase in the acetylation of eukaryotic translation initiation factor 5A, a physiological substrate of SIRT2. Importantly, NPD11033 failed to inhibit defatty-acylase activity of SIRT2, despite its potent inhibitory effect on its deacetylase activity. Thus, NPD11033 will serve as a useful tool for both developing novel anti-cancer agents and elucidating the role of SIRT2 in various cellular biological processes.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

PubMed: 29685974
DOI: 10.1098/rstb.2017.0070

Experimental method

X-RAY DIFFRACTION (2 Å)