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

DOI: 10.1042/BJ20131272

Authors: Vladimir s. Borodkin (University of Dundee) , Marianne Schimpl (University of Dundee) , Mehmet Gundogdu (University of Dundee) , Karim Rafie (University of Dundee) , Helge Dorfmueller (University of Dundee) , David Robinson (University of Dundee) , Daniel Van Aalten (University of Dundee)
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

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.

Journal Keywords: bisubstrate analogue inhibitor; glycosyltransferase; O-GlcNAc; rational drug design

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 23/09/2014 16:05

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)