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

Vladimir S Borodkin; Marianne Schimpl; Mehmet Gundogdu; Karim Rafie; Helge C Dorfmueller; David A. Robinson; Daan M F van Aalten

doi:10.1042/BJ20131272

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

Vladimir S Borodkin, Marianne Schimpl, Mehmet Gundogdu, Karim Rafie, Helge C Dorfmueller, David A. Robinson, Daan M F van Aalten (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

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.

Original language	English
Pages (from-to)	497-502
Number of pages	6
Journal	Biochemical Journal
Volume	457
Issue number	3
DOIs	https://doi.org/10.1042/BJ20131272
Publication status	Published - 1 Feb 2014

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10.1042/BJ20131272

Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)
van Aalten, D.
Medical Research Council
1/11/09 → 31/10/14
Project: Research
Aref#d: 21318. Molecular Mechanisms of O-GlcNAc Signalling (Senior Fellowship Renewal)
van Aalten, D.
Wellcome Trust
1/06/09 → 29/02/16
Project: Research

Developing O-GlcNAc transferase inhibitors - insights from substrate recognition
Author: Rafie, K., 2017
Supervisor: van Aalten, D. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy

File
Understanding tetratricopeptide repeats of O-GlcNAc transferase
Author: Gundogdu, M., 2017
Supervisor: van Aalten, D. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy

File

Cite this

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

author = "Borodkin, {Vladimir S} and Marianne Schimpl and Mehmet Gundogdu and Karim Rafie and Dorfmueller, {Helge C} and Robinson, {David A.} and {van Aalten}, {Daan M F}",

year = "2014",

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day = "1",

doi = "10.1042/BJ20131272",

language = "English",

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pages = "497--502",

journal = "Biochemical Journal",

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T1 - Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors

AU - Borodkin, Vladimir S

AU - Schimpl, Marianne

AU - Gundogdu, Mehmet

AU - Rafie, Karim

AU - Dorfmueller, Helge C

AU - Robinson, David A.

AU - van Aalten, Daan M F

PY - 2014/2/1

Y1 - 2014/2/1

N2 - 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.

AB - 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.

U2 - 10.1042/BJ20131272

DO - 10.1042/BJ20131272

M3 - Article

C2 - 24256146

SN - 0264-6021

VL - 457

SP - 497

EP - 502

JO - Biochemical Journal

JF - Biochemical Journal

IS - 3

ER -

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

Abstract

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Projects

Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)

Aref#d: 21318. Molecular Mechanisms of O-GlcNAc Signalling (Senior Fellowship Renewal)

Student theses

Developing O-GlcNAc transferase inhibitors - insights from substrate recognition

Understanding tetratricopeptide repeats of O-GlcNAc transferase

Cite this