2008 Scientific Report

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Van Andel Research Institute | Scientific Report H. Eric Xu, Ph.D. Laboratory of Structural Sciences Dr. Xu went to Duke University and the University of Texas Southwestern Medical Center, where he earned his Ph.D. in molecular biology and biochemistry. Following a postdoctoral fellowship with Carl Pabo at MIT, he moved to GlaxoWellcome in 1996 as a research investigator of nuclear receptor drug discovery. Dr. Xu joined VARI as a Senior Scientific Investigator in July 2002 and was promoted to Distinguished Scientific Investigator in March 2007. Staff Students Visiting Scientist Abhishek Bandyopadhyay, Ph.D. Jiyuan Ke, Ph.D. Schoen Kruse, Ph.D. Raghu Malapaka, Ph.D. Karsten Melcher, Ph.D. Augie Pioszak, Ph.D. David Tolbert, Ph.D. Yong Xu, Ph.D. Chenghai Zhang, Ph.D. X. Edward Zhou, Ph.D. Jennifer Daugherty, B.S. Amanda Kovach, B.S. Naomi Parker, B.S. Kelly Powell, B.S. Cee Wah Chan Aoife Conneely Xiang Gao Mien Nguyen Rachel Talaski Peipei Zhong Ross Reynolds, Ph.D. 76
VARI | 2008 Research Interests Our laboratory uses multidisciplinary approaches to study the structures and functions of protein complexes that play key roles in major signaling pathways. Currently we are focusing on three families of proteins: nuclear hormone receptors, the Met tyrosine kinase receptor, and G protein–coupled receptors, because beyond their fundamental roles in biology, these proteins are important drug targets for many human diseases. Nuclear hormone receptors The nuclear hormone receptors form a large family comprising ligand-regulated and DNA-binding transcription factors. The family includes receptors for classic steroid hormones such as estrogen, progesterone, androgens, and glucocorticoids, as well as receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. These classic receptors are among the most successful targets in the history of drug discovery: every receptor has one or more cognate synthetic ligands being used as medicines. The nuclear receptors also include a class of “orphan” receptors for which no ligand has been identified. In the last several years, we have developed the following projects centering on the structural biology of nuclear receptors. Peroxisome proliferator–activated receptors The peroxisome proliferator–activated receptors (PPARa, d, and g) are key regulators of glucose and fatty acid homeostasis and as such are important therapeutic targets for treating cardiovascular disease, diabetes, and cancer. We have determined crystal structures of each PPAR’s ligand-binding domain (LBD) bound to diverse ligands including fatty acids, the lipid-lowering fibrate drugs, and a new generation of anti-diabetic drugs, the glitazones. We have also determined the crystal structures of these receptors bound to coactivators or co-repressors. We are developing approaches to the structures of large PPAR fragment/DNA complexes. Human glucocorticoid and mineralocorticoid receptors The human glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are classic steroid hormone receptors that are key to a wide spectrum of human physiology, including immune/inflammatory responses, metabolic homeostasis, and control of blood pressure. Both are well-established drug targets. GR ligands such as dexamethasone (Dex) and fluticasone propionate (FP) are used to treat asthma, leukemia, and autoimmune diseases; MR ligands such as spironolactone and eplerenone are used to treat hypertension and heart failure. The discovery of highly potent and more-selective ligands for GR and MR is an important goal of pharmaceutical research. We have determined a crystal structure of the GR LBD bound to dexamethasone and the MR LBD bound to corticosterone, both of which are in complex with a coactivator peptide motif. These structures provide a detailed basis for the specificity of hormone recognition and coactivator assembly by GR and MR. Currently we are studying receptor-ligand interactions by crystallizing GR and MR with various steroid or nonsteroid ligands. In collaboration with Brad Thompson and Raj Kumar at the University of Texas Medical Branch at Galveston, we are also extending our studies to the structure of a large GR fragment bound to DNA. 77
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2008 Scientific Report

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