No group of proteins is arguable more critical for human health than the nuclear receptors that transmit hormonal signals into cellular responses. Our labs are united in a common goal of understanding the structure and function of nuclear receptors and their roles in controlling gene expression. An important facet of understanding nuclear receptor function involves elucidating the structure and dynamics of receptor activation. For the first time, NMR, X-ray crystallography and synthetic chemistry will be used in conjunction with cellular and biochemical assays to link structure to function for three nuclear receptors. Our proposal addresses three components of nuclear receptor structure and biology; 1) the structure of nuclear receptors, 2) the dynamics and structure of hormone interaction with receptors, and 3) the interactions of portions of the co-activator protein with the hormone-binding domain of a receptor. Our structural studies on nuclear receptors will include the regulatory protein, Steroidogenic factor-1 ( (SF-1) and heteromeric complexes of nuclear receptors and their partners. Studies on SF-1 should help to define similarities and differences between liganded receptors (thyroid hormone and estrogen receptors) and orphan receptors. The atomic and dynamic information of hormone binding and co-activator binding should provide mechanistic insight into the action of nuclear accessory proteins in defining specificity. By determining the structural underpinnings of different responses elicited by receptor isoforms (liganded, phosphorylated, or bound by accessory proteins), we should begin to delineate show complex molecular crosstalk integrates hormone and receptor signaling. Such information should also provide a greater appreciation as to how specificity of a hormone response is to determined. Ultimately, our studies will provide a structural basis to explain the coupling of hormone signaling and gene expression. Finally, our plans to link combinatorial chemistry with the structure and function of nuclear receptors should allow for development of new reagents with a potential use in human therapeutics.
