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26 Jan 2014

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 C3 linker and retained substrate-binding modes, and binds the enzyme with micromolar affinity, inhibiting glycosyltransfer on to protein and peptide substrates.

Vladimir S. Borodkin*, Marianne Schimpl*, Mehmet Gundogdu*, Karim Rafie*, Helge C. Dorfmueller*†, David A. Robinson‡ and Daan M. F. van Aalten*†1

*MRC Protein Phosphorylation und Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K., †Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K., and ‡Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.