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Fraydoon
Rastinejad
Degree(s): Ph.D. Graduate School: University of Pennsylvania Primary Appointment: Professor of Pharmacology Research Interests: Analysis of Nuclear Receptor Complexes with DNA and Ligands Email Address: fr9c@virginia.edu |
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Biomedical Sciences Graduate Program(s) Research Description My laboratory studies the nuclear hormone receptor family using modern tools from molecular biology , cell biology and structural biology , including X-ray crystallography. The overall goal is to elucidate the structural and functional properties of these transcription factors for the purpose of drug discovery and drug development. The nuclear receptors include steroid receptors such as the estrogen receptor , androgen receptor , glucocorticoid receptor , and a group of non-steroid receptors such as thyroid hormone receptor , the retinoid receptors and the peroxisome proliferators activated receptors (PPARs). The steroid receptors are validated drug targets for prostate cancer , breast cancer , and inflammatory diseases , while the non-steroid receptors are validated drug targets for diabetes and metabolic disorders and other physiological dysfunctions. Our research methods are broad in nature so that the physiology and pharmacology of these receptors can be adequately addressed. Receptor-Ligand interactions The nuclear receptors have central hydrophobic pockets to which ligands and synthetic molecules can bind directly , altering receptor function as gene specific transcriptional regulators. Current drugs on the market target a variety of nuclear receptors , including the steroid receptors (estrogen and androgen) , the thyroid hormone receptor , the PPARs and retinoid receptors. However , late stage clinical trials are also now underway for drugs that target FXR , LXR and other receptors which regulate atherosclerosis , heart disease , obesity and diabetes. Our research program is actively engaged in identifying and characterizing new lead molecules for these receptors using both chemical screening and structure-based design approaches coupled with appropriate physiological studies. As we identify the new ligands and generate new lead compounds , we employ cellular and biochemical assays to characterize their properties in detail , and further use them in X-ray crystallography studies to visualize the way in which they bind to the receptor pockets. (See Mi et al. Mol Cell 2003 for an example of such work , as well as Chandra , V. et al. 2008 (in press)). Protein-DNA interactions: The steroid receptors contain a central , highly conserved , DNA-binding domain consisting of a dual zinc-finger fold which allows them to directly bind to promoter elements as homo- and heterodimers. RXR , the retinoic X receptor , is a common heterodimerization partner for many nuclear receptors. We have studied the crystal structures of several RXR- heterodimers bound to their DNA elements. These studies have made it possible to understand the principles with which specific DNA sequences are recognized and selected , as well as the manner by which receptors coordinate their functional properties by dimerization. (See Devarakonda et al.. EBMO J. 2003 for example of this work). More recently , we are examining the manner in which nuclear receptors bind to chromatin regulatory factors , including co-activator and co-repressor proteins. Orphan Nuclear Receptors Our laboratory is also working on identifying the ligands and biochemical pathways controlled by the so-called “Orphan” receptors in the family , which currently have unknown function. We have recently shown the nuclear receptor Rev-Erb uses heme (iron-porphyrin IX) as its endogenous ligand (see Raguhram et al. , Nature Structural Molecular Biology , 2007 as an example). Rev-Erb regulates the circadian rhythm by controlling the expression of Bmal1 and other critical components. We are further studying Rev-Erb and other orphan receptors to better understand the role of the ligands in mediating biochemical pathways linked to human diseases , including depression and anxiety disorders. |