5NPR

The human O-GlcNAc transferase in complex with a thiol-linked bisubstrate inhibitor

5NPR の概要

• エントリーDOI: 10.2210/pdb5npr/pdb
• 分子名称: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, bisubstrate inhibitor, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: o-glcnac transferase, gt-b, rossman-fold, active site, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81675.15

構造登録者

Rafie, K.,van Aalten, D.M.F. (登録日: 2017-04-18, 公開日: 2018-05-16, 最終更新日: 2024-11-20)

主引用文献

Rafie, K.,Gorelik, A.,Trapannone, R.,Borodkin, V.S.,van Aalten, D.M.F.
Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.
Bioconjug. Chem., 29:1834-1840, 2018

PubMed Abstract: O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational modification on the nucleocytoplasmic proteome. We report the development of S-linked UDP-peptide conjugates as potent bisubstrate OGT inhibitors. These compounds were assembled in a modular fashion by photoinitiated thiol-ene conjugation of allyl-UDP and optimal acceptor peptides in which the acceptor serine was replaced with cysteine. The conjugate VTPVC(S-propyl-UDP)TA ( K = 1.3 μM) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant OGT inhibitors. A crystal structure of human OGT with the inhibitor revealed mimicry of the interactions seen in the pseudo-Michaelis complex. Furthermore, a fluorophore-tagged derivative of the inhibitor works as a high affinity probe in a fluorescence polarimetry hOGT assay.

PubMed: 29723473
DOI: 10.1021/acs.bioconjchem.8b00194

実験手法

X-RAY DIFFRACTION (1.85 Å)