All ETDs from UAB

Advisory Committee Chair

Donald D Muccio

Advisory Committee Members

Wayne J Brouillette

David E Graves

Clinton J Grubbs

Bingdong Sha

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences


Retinoid X receptors (RXRs) are ligand-dependent transcription factors which belong to the nuclear receptor (NR) superfamily. When a ligand binds to RXRs, it activates the protein allosterically for the recruitment of coactivator proteins and enhancement of gene transcription. RXRs form either homodimers or heterodimers with numerous other NRs. Thus, RXRs are involved in many signaling pathways in vivo. 9cRA, Targretin and UAB retinoids are RXR agonists and found to be effective agents to prevent and treat cancers. The structures of retinoid-bound RXRs will be helpful in designing new retinoids. This dissertation focuses on structural studies of the human retinoid X receptor alpha-ligand binding domain (hRXRα-LBD) bound to retinoids and the coactivator peptide GRIP-1. First, the structure of hRXRα-LBD bound to 9cRA and GRIP-1 was determined by X-ray crystallography and compared to the previously reported structure of hRXRα-LBD:9cRA without GRIP-1. It was found GRIP-1 binding caused structural changes on H11 and H12 of the holo-hRXRα-LBD. Second, the crystal structures of hRXRα-LBD bound to either 9cUAB30 or Targretin in the presence of GRIP-1 were solved. Both structures were similar to the structure of the hRXRα-LBD:9cRA:GRIP-1 complex. ITC measurements of the GRIP-1 binding to hRXRα-LBD with 9cRA, Targretin and 9cUAB30 were very similar except for the heat capacity change. In the next two chapters, crystal structures of hRXRα-LBD bound to class I or to class II UAB retinoids and GRIP-1 were reported. Protein structures of these complexes were similar to each other and to the structures containing 9cRA and Targretin. The ligand binding pockets of the hRXRα-LBD containing these UAB retinoids were analyzed. Small structural changes were found between GRIP-1 and the hRXRα-LBD containing the class II UAB retinoids. In summary, this dissertation reports the effects of these structurally unrelated retinoids on the conformation of hRXRα-LBD and on the nature of the coactivator peptide binding site on the surface of hRXRα-LBD. These studies strengthen our understanding of how different retinoids influence the hRXRα-LBD structure, and it may provide helpful insight into designing new RXR-selective retinoids.



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