Liver receptor homolog 1 (LRH-1) is a nuclear hormone receptor that acts as an important regulator of lipid metabolism, reverse cholesterol transport, and glucose sensing and homeostasis. As such, LRH-1 represents a novel therapeutic target for metabolic diseases, such as diabetes. LRH-1 binds to phospholipids (PLs), but until recently, the role of PLs in receptor activation was unclear. Recent studies identified dilauroylphosphatidylcholine (DLPC) as a specific LRH-1 agonist with potent anti-diabetic effects. Despite this therapeutic potential, mechanisms through which LRH-1 is regulated by ligands remain poorly understood. The discovery that LRH-1 is regulated by PL ligands reveals an exciting potential to tune LRH-1 activity for treatment of metabolic diseases. However, PLs (such as DLPC) are labile and not suitable for clinical use, necessitating the development of small molecule agonists. This has proved challenging thus far, since very few small molecules are capable of displacing endogenous lipids from the large, lipophilic binding pocket. Recent preliminary studies in our lab have characterized a potent class of small molecules that are capable of this feat. The overall goal of this proposal is to understand mechanisms through which LRH-1 is activated by synthetic ligands. X-ray crystallography combined with hydrogen deuterium exchange chromatography mass spectrometry and a host of biochemical and cellular techniques will be used to address this goal in a series of two Aims.
Specific Aim 1 : To determine structural characteristics of LRH-1 small molecule agonists important for binding, activation, and orientation in the binding pocket.
Specific Aim 2 : To elucidate mechanisms driving activation of LRH-1 by small molecule agonists. This work will offer insights into mechanisms through which LRH-1 is regulated by small molecules and will provide strategies for the rational design of more effective LRH-1 agonists. Such agonists would be invaluable pharmacological tools to probe LRH-1 biology and have great potential for treatment of metabolic diseases, such as diabetes.
Liver receptor homolog 1 (LRH-1) is a nuclear hormone receptor that acts as an important regulator of lipid and glucose metabolism. Developing small molecule modulators for LRH-1 would be highly beneficial as both research tools to understand LRH-1 biology and as potential therapeutics for metabolic diseases, such as diabetes. This proposal addresses challenges in the field with the development of small molecule agonists using structural, dynamical, and biochemical approaches to understand mechanisms through which LRH-1 is regulated by synthetic ligands.
| Flynn, Autumn R; Mays, Suzanne G; Ortlund, Eric A et al. (2018) Development of Hybrid Phospholipid Mimics as Effective Agonists for Liver Receptor Homologue-1. ACS Med Chem Lett 9:1051-1056 |
| Mays, Suzanne G; Okafor, C Denise; Tuntland, Micheal L et al. (2017) Structure and Dynamics of the Liver Receptor Homolog 1-PGC1? Complex. Mol Pharmacol 92:1-11 |
| Mays, Suzanne G; Okafor, C Denise; Whitby, Richard J et al. (2016) Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists. J Biol Chem 291:25281-25291 |
