3TAX

A Neutral Diphosphate Mimic Crosslinks the Active Site of Human O-GlcNAc Transferase

3TAX の概要

• エントリーDOI: 10.2210/pdb3tax/pdb
• 分子名称: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, Casein kinase II subunit alpha, URIDINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: thiocarbamate crosslink, covalent inhibitor, gylcosyltransferase inhibitor, o-glcnac transferase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: O15294
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 165998.77

構造登録者

Lazarus, M.B.,Jiang, J.,Pasquina, L.,Sliz, P.,Walker, S. (登録日: 2011-08-04, 公開日: 2011-11-16, 最終更新日: 2024-10-30)

主引用文献

Jiang, J.,Lazarus, M.B.,Pasquina, L.,Sliz, P.,Walker, S.
A neutral diphosphate mimic crosslinks the active site of human O-GlcNAc transferase.
Nat.Chem.Biol., 8:72-77, 2011

PubMed Abstract: Glycosyltransferases (Gtfs) catalyze the formation of a diverse array of glycoconjugates. Small-molecule inhibitors to manipulate Gtf activity in cells have long been sought as tools for understanding Gtf function. Success has been limited because of challenges in designing inhibitors that mimic the negatively charged diphosphate substrates. Here we report the mechanism of action of a small molecule that inhibits O-linked N-acetylglucosamine transferase (OGT), an essential human enzyme that modulates cell signaling pathways by catalyzing a unique intracellular post-translational modification, β-O-GlcNAcylation. The molecule contains a five-heteroatom dicarbamate core that functions as a neutral diphosphate mimic. One dicarbamate carbonyl reacts with an essential active site lysine that anchors the diphosphate of the nucleotide-sugar substrate. A nearby cysteine then reacts with the lysine adduct to form a carbonyl crosslink in the OGT active site. Though this unprecedented double-displacement mechanism reflects the unique architecture of the OGT active site, related dicarbamate scaffolds may inhibit other enzymes that bind nucleotide-containing substrates.

PubMed: 22082911
DOI: 10.1038/nchembio.711

実験手法

X-RAY DIFFRACTION (1.88 Å)