Publication Date:
2011-01-18
Description:
The essential mammalian enzyme O-linked beta-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 (2.8 A resolution) and as a ternary complex with UDP and a peptide substrate (1.95 A). 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064491/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064491/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lazarus, Michael B -- Nam, Yunsun -- Jiang, Jiaoyang -- Sliz, Piotr -- Walker, Suzanne -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM076710/GM/NIGMS NIH HHS/ -- R01 GM076710-01A1/GM/NIGMS NIH HHS/ -- R01 GM076710-02/GM/NIGMS NIH HHS/ -- R01 GM076710-03/GM/NIGMS NIH HHS/ -- R01 GM076710-04/GM/NIGMS NIH HHS/ -- R01 GM078477/GM/NIGMS NIH HHS/ -- R01 GM078477-03/GM/NIGMS NIH HHS/ -- R01 GM078477-04/GM/NIGMS NIH HHS/ -- R01 GM094263/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jan 27;469(7331):564-7. doi: 10.1038/nature09638. Epub 2011 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21240259" target="_blank"〉PubMed〈/a〉
Keywords:
Catalytic Domain
;
Humans
;
*Models, Molecular
;
N-Acetylglucosaminyltransferases/*chemistry/metabolism
;
Peptides/chemistry/metabolism
;
Protein Structure, Tertiary
;
Uridine Diphosphate/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
