2VVS

BtGH84 structure in complex with PUGNAc

2VVS の概要

• エントリーDOI: 10.2210/pdb2vvs/pdb
• 関連するPDBエントリー: 2CHN 2CHO 2J47 2J4G 2JIW 2VVN
• 分子名称: O-GLCNACASE BT_4395, O-(2-ACETAMIDO-2-DEOXY D-GLUCOPYRANOSYLIDENE) AMINO-N-PHENYLCARBAMATE (3 entities in total)
• 機能のキーワード: hydrolase, inhibitor, glycoside hydrolase, o-glcnac
• 由来する生物種: BACTEROIDES THETAIOTAOMICRON VPI-5482
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 84941.25

構造登録者

Macauley, M.S.,Bubb, A.,Martinez-Fleites, C.,Davies, G.J.,Vocadlo, D.J. (登録日: 2008-06-11, 公開日: 2008-09-30, 最終更新日: 2023-12-13)

主引用文献

Macauley, M.S.,Bubb, A.,Martinez-Fleites, C.,Davies, G.J.,Vocadlo, D.J.
Elevation of Global O-Glcnac Levels in 3T3-L1 Adipocytes by Selective Inhibition of O-Glcnacase Does not Induce Insulin Resistance
J.Biol.Chem., 283:34687-, 2008

PubMed Abstract: The O-GlcNAc post-translational modification is considered to act as a sensor of nutrient flux through the hexosamine biosynthetic pathway. A cornerstone of this hypothesis is that global elevation of protein O-GlcNAc levels, typically induced with the non-selective O-GlcNAcase inhibitor PUGNAc (O-(2-acetamido-2-deoxy-D-glycopyranosylidene) amino-N-phenylcarbamate), causes insulin resistance in adipocytes. Here we address the potential link between elevated O-GlcNAc and insulin resistance by using a potent and selective inhibitor of O-GlcNAcase (NButGT (1,2-dideoxy-2'-propyl-alpha-D-glucopyranoso-[2,1-D]-Delta 2'-thiazoline), 1200-fold selectivity). A comparison of the structures of a bacterial homologue of O-GlcNAcase in complex with PUGNAc or NButGT reveals that these inhibitors bind to the same region of the active site, underscoring the competitive nature of their inhibition of O-GlcNAcase and the molecular basis of selectivity. Treating 3T3-L1 adipocytes with NButGT induces rapid increases in global O-GlcNAc levels, but strikingly, NButGT treatment does not replicate the insulin desensitizing effects of the non-selective O-GlcNAcase inhibitor PUGNAc. Consistent with these observations, NButGT also does not recapitulate the impaired insulin-mediated phosphorylation of Akt that is induced by treatment with PUGNAc. Collectively, these results suggest that increases in global levels of O-GlcNAc-modified proteins of cultured adipocytes do not, on their own, cause insulin resistance.

PubMed: 18842583
DOI: 10.1074/JBC.M804525200

実験手法

X-RAY DIFFRACTION (2.24 Å)