6NR0

SIRT2(56-356) with covalent intermediate between mechanism-based inhibitor Glucose-TM-1beta and 1'-SH ADP-ribose

6NR0 の概要

• エントリーDOI: 10.2210/pdb6nr0/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, N~2~-[3-(2-hydroxyethoxy)propanoyl]-N-phenyl-N~6~-tetradecanethioyl-L-lysinamide, ... (8 entities in total)
• 機能のキーワード: inhibitor, intermediate, deacylase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75381.14

構造登録者

Price, I.R.,Hong, J. (登録日: 2019-01-22, 公開日: 2020-01-22, 最終更新日: 2023-10-11)

主引用文献

Hong, J.Y.,Price, I.R.,Bai, J.J.,Lin, H.
A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors.
Acs Chem.Biol., 14:1802-1810, 2019

PubMed Abstract: Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.

PubMed: 31373792
DOI: 10.1021/acschembio.9b00384

実験手法

X-RAY DIFFRACTION (2.45 Å)