Structural basis for nuclear receptor allostery
This molecular and biomedical science honours project will give you a better understanding of general receptor allostery as well as structure guided drug design.
Nuclear Receptors (NRs) are transcription factors that are modulated by small molecules such as hormones. Examples of this protein family include Peroxisome Proliferator-Activated Receptor (PPARα,δ,γ), Estrogen Receptor (ERα and ERβ), Retinoid X Receptor (RXR), and Thyroid Receptor (TR).
Work in my lab is focused largely on the PPARs and ERs. PPARγ is a NR that forms a heterodimer with RXR and regulates genes involved in energy, carbohydrate, and lipid metabolism.
Thiazolidinediones (TZDs) such as rosiglitazone are synthetic agonists of PPARγ which target adipose tissue and are prescribed as antidiabetic agents due to their improvement of insulin sensitivity. In contrast, ER is the target of the agonist hormone estrogen.
Synthetic antagonists of estrogen have been employed in breast cancer treatment. SERMs (Selective Estrogen Receptor Modulators) have largely been focused on selectively targeting and inhibiting the proliferative effect of ERα. The best examples are tamoxifen and raloxifene used in the treatment of breast cancer.
To gain a full understanding of NR mechanism we must probe the allosteric signal on an atomic level beginning from ligand binding to transcriptional output. In my lab, we use a multidisciplinary approach in understanding NR allostery with the goal of developing new therapeutics for respective disorders such as diabetes and cancer.
Honours projects in this area of research will include structural studies on one nuclear receptor (per student). Goals of the projects will include gaining a better understanding of general receptor allostery as well as structure guided drug design.
Techniques employed will include cloning, cell growth and protein expression, protein purification, crystallisation, and X-ray crystallographic structure determination. Additional techniques may include compound library screening, virtual compound screening, and transcriptional assays.