S-301

Fine Tuning the Activity of Liver Receptor Homologue -1, an Orphan Nuclear Receptor

Manish Pathak, Eric Ortlund

Emory University School of Medicine, Atlanta, Ga, United States

Liver Receptor Homologue-1 (LRH-1), an orphan nuclear receptor, center to the breast and
colon cancer development has also been implicated in Diabetes, Obesity, Bileacid
homeostasis and Steroidogenesis. Being at the center of multiple pathways raises the
pharmaceutical importance of the ligand on the consequent impact. Unlike human Lrh-1
Ligand Binding Domain (hLrh-1), mouse LRH-1 (mLrh-1) and Drosophila ortholog Ftz-F1 use
distinct strategy to abolish ligand binding to stay constitutive. While, Ftz-f1 redirects helix H6
into its own pocket, mLRH-1 closes the pocket mouth. Borrowing six residues from mLrh-1
mouth into hLrh-1 converted it into an unliganded & unrecruited form akin to mLRH-1 shown
by x-ray crystal structure, which retained the ability to recruit coactivator in vitro. The change
induces a series of conformational changes in the Lrh-1 mouth that accommodates the
phosphate head group.

Here we show the ligand modulated coactivator recruitment by Lrh-1. Apparently constitutive,
phospholipid stripped hLRH-1 recruits co-activator 13.4 times weaker whereas choline
enhances the recruitment suggesting a hierarchy of ligands involved. Reduced activity with
liver extract prompts us to envisage a theory of fine tuning of the ligand mediated coactivator
recruitment instead of binary active-inactive forms. The putative hypothesis refers that lower
activity is a good activity. Identification of few ligands using mass-spectroscopy will also be
explained. Moreover, change in the secondary structure content of apo LRH-1 seen by
Circular Dichroism adds into the fine-tune theory from molecular dynamics point of view
signifying controlled execution highly imperative. A diverse comparative study with other
nuclear receptors highlight the versatility associated with LRH-1 and its multifaceted role in
cellular system at different stages of development.