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

Borodkin VS, Schimpl M, Gundogdu M, Rafie K, Dorfmueller HC, Robinson DA, van Aalten DM - Biochem. J. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: *MRC Protein Phosphorylation und Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

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

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Related in: MedlinePlus

Synthesis of UDP–peptide conjugates and ‘linker-only’ peptide(a) Microwave-assisted Fmoc SPPS (solid-phase peptide synthesis); (b) (i) 13, CDI (1,1′-carbonylbisimidazole), DMF (dimethylformamide), room temperature, 20 h then methanol then 8a/8b, room temperature 16 h; (c) methanol, triethylamine, water, room temperature, 16 h then HPLC.
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S2: Synthesis of UDP–peptide conjugates and ‘linker-only’ peptide(a) Microwave-assisted Fmoc SPPS (solid-phase peptide synthesis); (b) (i) 13, CDI (1,1′-carbonylbisimidazole), DMF (dimethylformamide), room temperature, 20 h then methanol then 8a/8b, room temperature 16 h; (c) methanol, triethylamine, water, room temperature, 16 h then HPLC.


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

Borodkin VS, Schimpl M, Gundogdu M, Rafie K, Dorfmueller HC, Robinson DA, van Aalten DM - Biochem. J. (2014)

Synthesis of UDP–peptide conjugates and ‘linker-only’ peptide(a) Microwave-assisted Fmoc SPPS (solid-phase peptide synthesis); (b) (i) 13, CDI (1,1′-carbonylbisimidazole), DMF (dimethylformamide), room temperature, 20 h then methanol then 8a/8b, room temperature 16 h; (c) methanol, triethylamine, water, room temperature, 16 h then HPLC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927924&req=5

S2: Synthesis of UDP–peptide conjugates and ‘linker-only’ peptide(a) Microwave-assisted Fmoc SPPS (solid-phase peptide synthesis); (b) (i) 13, CDI (1,1′-carbonylbisimidazole), DMF (dimethylformamide), room temperature, 20 h then methanol then 8a/8b, room temperature 16 h; (c) methanol, triethylamine, water, room temperature, 16 h then HPLC.
Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: *MRC Protein Phosphorylation und Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

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

Show MeSH
Related in: MedlinePlus