# Mechanistic studies of corepressor-mediated PPARγ transcriptional repression

> **NIH NIH R01** · SCRIPPS FLORIDA · 2020 · $505,180

## Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that
regulates cellular differentiation, adipogenesis, and insulin resistance by recruiting transcriptional coregulator
proteins (corepressor and coactivator proteins) to target gene promoters in a ligand-dependent manner.
Structure-function approaches have defined how the transcriptionally active structural conformation and
coactivator-selective functions of PPARγ are influenced by agonist ligands. However, little is known about the
transcriptionally repressive conformation and corepressor-selective functions of PPARγ. Our long-term goal is
to close this knowledge gap by defining how different pharmacological PPARγ ligands influence the structure
and function of PPARγ between transcriptionally active and repressive states. In preliminary studies, we solved
crystal structures of the PPARγ ligand-binding domain (LBD) in a transcriptionally repressive state using a
unique corepressor-selective ligand, revealing a unique structural conformation that we have started to validate
using solution NMR methods. In this project, we will use mechanistic studies to define how small molecule
ligands impact PPARγ activation and repression on the molecular, structural, and cellular levels. Successful
outcomes from our studies will define the activity-dependent conformational ensemble of the PPARγ LBD,
develop ligands with enhanced corepressor-selective activity, and determine the molecular mechanisms by
which corepressor-selective repressive ligands modulate PPARγ cellular functions.

## Key facts

- **NIH application ID:** 9959943
- **Project number:** 1R01DK124870-01
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Douglas Kojetin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,180
- **Award type:** 1
- **Project period:** 2020-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959943

## Citation

> US National Institutes of Health, RePORTER application 9959943, Mechanistic studies of corepressor-mediated PPARγ transcriptional repression (1R01DK124870-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959943. Licensed CC0.

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