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

DOI: 10.1042/BJ20131272 DOI Help

Authors: Vladimir s. Borodkin (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.) , Marianne Schimpl (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.) , Mehmet Gundogdu (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.) , Karim Rafie (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.) , Helge Dorfmueller (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.) , David Robinson (Drug Discovery Unit, College of Life Sciences, University of Dundee, U.K.) , Daniel Van Aalten (MRC Protein Phosphorylation und Ubiquitylation Unit, University of Dundee, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 457 , PAGES 497 - 502

State: Published (Approved)
Published: February 2014
Diamond Proposal Number(s): 8268

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

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