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

ABSTRACT: 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.

SUBMITTER: Borodkin VS 

PROVIDER: S-EPMC3927924 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Borodkin Vladimir S VS   Schimpl Marianne M   Gundogdu Mehmet M   Rafie Karim K   Dorfmueller Helge C HC   Robinson David A DA   van Aalten Daan M F DM  

The Biochemical journal 20140201 3

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 substra  ...[more]

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