# Beyond the Active Site: Structure Informed Novel Regulatory Mechanisms and Functional Modulation of O-GlcNAc Transferase

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $397,900

## Abstract

Abstract
 The essential human enzyme O-GlcNAc transferase (OGT) catalyzes a unique type of intracellular protein
glycosylation called O-GlcNAcylation. In response to nutrient levels and stress, OGT dynamically regulates a
variety of physiological and pathological processes including the “Warburg effect” in cancer cells and insulin
resistance in diabetes. Previous studies on the OGT active site have made fundamental discoveries on its
catalytic mechanism and substrate interactions. However, how OGT regulates protein- and site-specific O-
GlcNAcylation remains unclear. This is due to a number of challenges including: 1) OGT glycosylates thousands
of proteins without a conserved sequence motif near the O-GlcNAc modification site, 2) a majority of O-
GlcNAcylation sites are found on intrinsically disordered regions (IDRs), 3) OGT typically binds proteins with
low/moderate affinity, and 4) a lack of OGT-protein complex structures. In our last funding period, we have made
strides in these areas through development of a suite of novel chemical probes that allow us to interrogate OGT
specific interactions with low/moderate affinity for structural, proteomic, and biochemical characterizations. This
proposal aims to make further conceptual and technical breakthroughs toward addressing these longstanding
challenges. It is expected that a better understanding of how OGT interacts with other proteins, particularly
through the regions beyond the OGT catalytic site, will be essential for understanding OGT’s functional regulation
at protein- and site-specific levels, filling major knowledge gaps between decades of biological observations of
OGT’s nutrient sensing and other regulatory roles, and will support the need to specifically modulate OGT
functions for biomedical applications.

## Key facts

- **NIH application ID:** 10914279
- **Project number:** 5R01GM121718-07
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jiaoyang Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,900
- **Award type:** 5
- **Project period:** 2017-08-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914279

## Citation

> US National Institutes of Health, RePORTER application 10914279, Beyond the Active Site: Structure Informed Novel Regulatory Mechanisms and Functional Modulation of O-GlcNAc Transferase (5R01GM121718-07). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/10914279. Licensed CC0.

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