# Full-length LRH-1 structural regulation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $346,000

## Abstract

LRH-1 (NR5A2) is a monomeric nuclear receptor involved in many aspects of liver physiology, including bile acid, cholesterol and glucose homeostasis. LRH-1 activation has beneficial effects on liver metabolism in pre-clinical mouse models. As nuclear receptors like LRH-1 have a very druggable ligand-binding pocket, LRH-1 has been targeted by many drug development efforts with great recent progress, however an LRH-1 agonist is still not available in the clinic. Like most other nuclear receptors, LRH-1 is composed of a DNA-binding domain and a ligand-binding domain, which are connected by a large unstructured Hinge domain. Classic nuclear receptor drug design has focused on the isolated ligand-binding domain, as the regulatory mechanism of this isolated domain is very well understood at the molecular level: binding of a hydrophobic small molecule allosterically alters ligand-binding domain recruitment of a transcriptional coregulator, which regulates nuclear receptor function. However, several lines of evidence suggest inter-domain communication exists between LRH-1 domains, regulating function. Understanding the structural biology behind this inter-domain communication might help LRH-1 drug design efforts, however technical challenges in applying crystallography or cryo-EM has prevented progress, despite great effort from several groups. We used an integrated structural approach to develop a low-resolution, but high confidence model of the intact, full-length LRH-1, using exclusively solution-based biophysical analyses and computational modeling (HDX, SAXS, chemical crosslinking, artificial amino acid benzophenone cross linking, Cys-Cys interdomain crosslinking, Rosetta and MD simulations). The model explains human patient mutations and structure-based mutations predicted to reside in the interface between the domains, which we show alter full length LRH-1 structure and function. Here, we propose to take advantage of this solution-based approach to address several long-standing questions in the field: Aim 1 determines how various ligands change full length LRH-1 interdomain communication. Aim 2 resolves how the SUMO module post-translational modification alters LRH-1 interdomain communication. Aim 3 identifies the genes effected by structure-based LRH-1 mutations in mouse liver and primary hepatocytes. Our current understanding of how LRH-1 structure is regulated is limited to studies of the individual domains. Without understanding how full-length LRH-1 is regulated, we cannot know if our current drug design efforts are taking full advantage of the entire therapeutic capacity of LRH-1.

## Key facts

- **NIH application ID:** 10034145
- **Project number:** 1R01GM138873-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Raymond Daniel Blind
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,000
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034145

## Citation

> US National Institutes of Health, RePORTER application 10034145, Full-length LRH-1 structural regulation (1R01GM138873-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10034145. Licensed CC0.

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