Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors

Authors: Borodkin, Vladimir S.; Schimpl, Marianne; Gundogdu, Mehmet; Rafie, Karim; Dorfmueller, Helge C.; Robinson, David A.; van Aalten, Daan M. F.; Biochemical Journal; (2014); 10.1042/bj20131272

Inhibitors of OGT (O-GlcNAc transferase) are valuable tools to study the cell biology of protein O-GlcNAcylation. We report OGT bisubstrate-linked inhibitors (goblins) in which the acceptor serine in the peptide VTPVSTA is covalently linked to UDP, eliminating the GlcNAc pyranoside ring. Goblin1 co-crystallizes with OGT, revealing an ordered C? linker and retained substrate-binding modes, and binds the enzyme with micromolar affinity, inhibiting glycosyltransfer on to protein and peptide substrates.