Structure of human O-GlcNAc transferase and its complex with a peptide substrate

Michael B. Lazarus, Yunsun Nam, Jiaoyang Jiang, Piotr Sliz, Suzanne Walker

Research output: Contribution to journalArticle

239 Scopus citations

Abstract

The essential mammalian enzyme O-linked β 2-N-acetylglucosamine transferase (O-GlcNAc transferase, here OGT) couples metabolic status to the regulation of a wide variety of cellular signalling pathways by acting as a nutrient sensor. OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phosphatases and histone-modifying proteins. Aberrant glycosylation by OGT has been linked to insulin resistance, diabetic complications, cancer and neurodegenerative diseases including Alzheimer-s. Despite the importance of OGT, the details of how it recognizes and glycosylates its protein substrates are largely unknown. We report here two crystal structures of human OGT, as a binary complex with UDP (2.8Å resolution) and as a ternary complex with UDP and a peptide substrate (1.95Å). The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region. This information will accelerate the rational design of biological experiments to investigate OGT-s functions; it will also help the design of inhibitors for use as cellular probes and help to assess its potential as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)564-569
Number of pages6
JournalNature
Volume469
Issue number7331
DOIs
StatePublished - Jan 27 2011

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Structure of human O-GlcNAc transferase and its complex with a peptide substrate'. Together they form a unique fingerprint.

  • Cite this