# Modulating Coregulator Preference of Liver Receptor Homolog-1 with Small Molecules

> **NIH NIH F31** · EMORY UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Liver receptor homolog-1 (LRH-1) is a nuclear receptor (NR) that has shown promise as an anti-diabetic
therapeutic in murine studies and regulates cholesterol transport, bile acid biosynthesis, steroidogenesis, and
glucose homeostasis, making it an attractive target for treating a variety of diseases. NRs are allosteric effectors,
transmitting ligand binding status to alter target gene expression by selectively recruiting coregulator enzymes
that modify chromatin and recruit transcriptional machinery. Although phospholipids are endogenous ligands of
LRH-1, my lab has used structure-activity relationship (SAR) studies to develop synthetic agonists that are more
useful for targeting this protein in experimental and clinical contexts. We have used a structure-guided approach
to directly contact residues in the binding pocket to produce compounds that bind and activate LRH-1 with low-
nanomolar potency. However, our understanding of how these small molecules drive LRH-1 activation
through altered coregulator preference remains limited, and work on our current series of agonists has
enhanced affinity of small molecules while minimally improving in-cell fold activation of LRH-1. How
LRH-1 senses ligand to recruit coregulators is poorly understood, as evidenced by our high-affinity small
molecules that do not efficiently drive coregulator association to enhance activation. Therefore, I will examine
how coregulator preference is influenced by synthetic agonist binding and make modifications to small molecules
that will directly target the LRH-1 activation function surface (AFS), the coregulator binding interface. I
hypothesize that synthetic agonists induce conformational changes favoring interaction with
coactivators and that LRH-1 activity can be modulated by directly altering AFS dynamics. In Aim 1, I will
examine the mechanism of ligand-mediated activation by determining how coregulator recruitment is influenced
by agonist binding. I will use fluorescence polarization (FP) and bioluminescence resonance energy transfer
(BRET) binding assays to test how small molecules and endogenous phospholipids alter coregulator preference.
I will then establish functional relevance for observed interactions using a luciferase reporter assay to examine
whether ligand-mediated activation of LRH-1 relies upon expression of these coregulators. In Aim 2, I will use a
structure-guided approach to make modifications that directly modulate AFS conformational dynamics. Using FP
competition and luciferase reporter assays, I will identify how modifications impact binding and in-cell activation
of LRH-1. Promising small molecules will be studied further with both X-ray crystallography and hydrogen
deuterium exchange coupled with mass spectrometry (HDX-MS) to examine how these modifications drive AFS
conformation and dynamics. The long-term goal of my work is to enhance design of small molecule modulators
of LRH-1 activity that will be useful for probing LRH-1 b...

## Key facts

- **NIH application ID:** 10134096
- **Project number:** 5F31DK122745-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Michael Lee Cato
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134096

## Citation

> US National Institutes of Health, RePORTER application 10134096, Modulating Coregulator Preference of Liver Receptor Homolog-1 with Small Molecules (5F31DK122745-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134096. Licensed CC0.

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