2VVN

BtGH84 in complex with NH-Butylthiazoline

2VVN の概要

• エントリーDOI: 10.2210/pdb2vvn/pdb
• 関連するPDBエントリー: 2CHN 2CHO 2J47 2J4G 2JIW
• 分子名称: O-GLCNACASE BT_4395, GLYCEROL, AMMONIUM ION, ... (5 entities in total)
• 機能のキーワード: glycoside hydrolase, complex, hydrolase, inhibitor, glycosidase
• 由来する生物種: BACTEROIDES THETAIOTAOMICRON
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 169782.57

構造登録者

He, Y.,Davies, G.J. (登録日: 2008-06-10, 公開日: 2008-07-01, 最終更新日: 2023-12-13)

主引用文献

Yuzwa, S.A.,Macauley, M.S.,Heinonen, J.E.,Shan, X.,Dennis, R.J.,He, Y.,Whitworth, G.E.,Stubbs, K.A.,Mceachern, E.J.,Davies, G.J.,Vocadlo, D.J.
A Potent Mechanism-Inspired O-Glcnacase Inhibitor that Blocks Phosphorylation of Tau in Vivo.
Nat.Chem.Biol., 4:483-, 2008

PubMed Abstract: Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K(i) = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

PubMed: 18587388
DOI: 10.1038/NCHEMBIO.96

実験手法

X-RAY DIFFRACTION (1.85 Å)