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2009 Scientific Report

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Van Andel Research

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 in 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 Scientists Abhishek Bandyopadhyay, Ph.D. Ajian He, 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 Holtrop, B.S. Amanda Kovach, B.S. Naomi Parker, B.S. Kelly Powell, B.S. Debra Guthrey Cee Wah Chen Aoife Conneely Xiang Gao Clara Jurecky Shiva Kumar Kuntal Pal Emily Popma Leonor Ruivo Rachel Talaski Xiaoyong Zhi Jun Li, Ph.D. Ross Reynolds, Ph.D. 72

VARI | 2009 Research Interests My major research interest is the structures and functions of protein/ligand complexes that play key roles in major hormone signaling pathways. My secondary research interest is to explore the structural information with a goal of developing therapeutic agents for treating human disease, including cancer and diabetes. Research in my group currently focuses on three areas— nuclear hormone receptors, the Met tyrosine kinase receptor, and G protein–coupled receptors—because these proteins, beyond their fundamental roles in biology, are important drug targets. Our studies use multidisciplinary approaches, including molecular and cellular biology, biochemistry, animal physiology, and X-ray crystallography. Nuclear hormone receptors Nuclear hormone receptors form a large family comprising ligand-regulated and DNA-binding transcriptional factors, including 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 synthetic ligands currently being used as medicines. In the last five 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. Millions of patients have benefited from treatment with the PPARg ligands rosiglitazone and pioglitazone for type II diabetes. To understand the molecular basis of ligand-mediated signaling by PPARs, we have determined crystal structures of each PPAR’s ligand-binding domain (LBD) bound to many diverse ligands, including fatty acids, the lipid-lowering fibrates, and a new generation of antidiabetic drugs, the glitazones. We have also determined the crystal structures of these receptors bound to coactivators or co-repressors, and that of PPARg bound to natural ligand-nitrated fatty acid. These structures provide a framework for understanding the mechanisms of PPAR agonists and antagonists, as well as the recruitment of coactivators and co-repressors. We have discovered a number of natural ligands of PPARg. The specific plan of this project is to test the physiological roles of these PPAR ligands in glucose and insulin regulation, to unravel their molecular and structural mechanisms of action, and to develop them as therapeutics for diabetes and dislipidemia treatment. Human glucocorticoid and mineralocorticoid receptors The human glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are classic steroid hormone receptors that have crucial effects on immune/inflammatory responses, metabolic homeostasis, and control of blood pressure. Both GR and MR are well-established drug targets, and drugs targeting these receptors are sold for more than billion annually. 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. However, the clinical use of these ligands is limited by undesirable side effects partly associated with their receptor cross-reactivity or low potency. Thus, the discovery of highly potent and more-selective ligands for GR (such ligands are called “dissociated glucocorticoids”, which can separate good effects from bad ones) remains an intensive goal of pharmaceutical research. Recently we determined the structure of GR bound to deacylcortivazol (DAC), which binds to GR with 200-fold more potency than cortisol, the physiological glucocorticoid. The GR DAC structure reveals that the GR ligand binding pocket can be expanded dramatically, to twice its normal size. This new pocket provides a tremendous opportunity for drug design and screening. Using a computational screen, we have identified several nonsteroidal ligands that like dissociated glucocorticoids in our cell-based assay. We are now running animal studies to confirm the physiological activities of these novel nonsteroidal ligands, which could lead to new methods of treating inflammation and autoimmune diseases. In addition, we plan to study the molecular and structural mechanisms of the dissociated glucocorticoids identified by our research. 73

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