All ETDs from UAB

Advisory Committee Chair

Natalia Kedishvili

Advisory Committee Members

Suzanne Lapi

Chad Petit

Peter Prevelige

Matthew Renfrow

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Nuclear receptors (NR) are ligand-activated transcription factors that are targets for drug discovery due to their ability to directly modulate gene expression. There are 48 NRs and approximately half of them require heterodimerization with retinoid X receptor (RXR) to function. Targretin (bexarotene) is an FDA-approved RXR specific (rexinoid) currently used to treat Cutaneous T-cell Lymphoma (CTCL); however, it causes hyperlipidemia toxicities. A functionally similar rexinoid developed at UAB, 9-cis-UAB30 (UAB30), is non-toxic and weak agonist in the liver. While UAB30 shows promise as a low toxicity chemopreventative drug, the mechanism of UAB30 action at the molecular level is poorly understood. By modifying UAB30, we have been able to understand how structurally similar rexinoids dynamically alter RXR in different regions. The standard NR-targeted drug design involves the characterization of ligand- ligand-binding domain (LBD) structural interactions through X-ray crystallography. While crucial in the design process, crystallographic structures are static snapshots of ligand-bound proteins that exist in solution, having dynamic molecular motions. In this dissertation, I used hydrogen deuterium exchange mass spectrometry to analyze rexinoid and coactivator binding-associated structural dynamics. I investigated the response of binding of several rexinoids in complex with RXRα-LBD, which gave insight into two rexinoid responses of binding. The first response involved decreased deuterium iii uptake (decreased dynamics) of helices 3 and 5. Decreased dynamics of these regions correlated with both potency and binding affinity of the rexinoid to RXRα-LBD. The second response was an increase in deuterium uptake (increase dynamics) of the C-terminal end of helix 3, helices 8 and 9, and the loop between helix 8 and 9. Part of the RXR homodimer interface displayed increased dynamics. We further investigated RXRα-LBD by incorporating a coactivator peptide. The ternary complexes of RXRα-LBD-rexinoid-coactivator displayed decreased dynamics in the ligand-binding pocket and coactivator binding sites. The accumulated profiles of various RXR complexes helped in understanding RXR’s mechanism of action.