Our Research

We are an interdisciplinary research group that utilizes structural biology, biochemical, biophysical, chemical biology, and cellular/molecular pharmacology methods to explore structure-function mechanisms of nuclear (hormone) receptor transcription factors.  Nuclear receptors are ligand-dependent transcription factors that function in part by recruiting chromatin remodeling machinery to promoter regions of target genes. Nuclear receptors exert powerful influences on all aspects of human physiology, and because their dysfunction is linked to many human diseases they are targets for more than 10% of FDA approved drugs. Our goal is to determine the structural mechanism of action of small molecule ligands (endogenous/natural ligands and synthetic ligands/drugs) that interact with (or bind) and affect the function of nuclear receptors.

 
 
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Conformational dynamics and function of the type 2 diabetes drug target PPARγ

A central tenet driving current PPARγ drug development is that synthetic ligands compete with natural endogenous ligands, including fatty acids and lipids, for binding to a canonical, orthosteric ligand-binding pocket (LBP) in the core of the ligand-binding domain (LBD) to pharmacologically regulate PPARγ activity. We have shown how the structural dynamics of PPARγ is affected by graded agonism — small molecules that robust or weakly activate PPARγ. More recently, we discovered a second or 'alternate' ligand binding site for current drugs and other small molecule chemical probes that interact with PPARγ.


Defining a ligand-binding pocket in the orphan nuclear receptor Nurr1

In the late 1980s, about half of the 48 human nuclear receptors were termed orphans because their endogenous ligands were unknown. Some of these orphan nuclear receptors have been since been “adopted” as their endogenous ligands have been discovered. However, the NR4As are thought to function independent of ligand because no endogenous ligands have been identified for these receptors. Furthermore, a crystal structure of Nurr1 indicated it lacks physical space within the conserved ligand-binding pocket region used by non-orphans nuclear receptors to bind natural ligands. Our recent studies show that Nurr1 can indeed bind a natural ligand — docosahexaneoic acid (DHA), an unsaturated fatty acid abundant in the brain — indicating there may yet be a physiological ligand to be identified for Nurr1.


Conformational allostery in RXR heterodimeric complexes

Retinoid X receptor (RXR) nuclear receptors are unique in that they interact (dimerize) with other nuclear receptors, such as PPARs and thyroid hormone receptors (TRs), to integrate distinct ligand-dependent signals through ligand binding to one or both nuclear receptor partners. We have uncovered dynamic activation mechanism by which RXR silences the ability of a TR ligand, but not a PPAR ligand, from activating transcription. We have also detailed a molecular pathway by which ligand binding to RXR's dimer partner allosterically influences the conformation of RXR. More recently, we have begun to explore how ligand and DNA binding to RXR heterodimeric complexes influences the recruitment of nuclear receptor coregulator proteins on the structural level.