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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 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 Glaxo Wellcome in 1996 as a research investigator of nuclear receptor drug discovery. Dr. Xu joined VARI in July 2002 and was promoted to Professor in March 2007. He is also the Primary Investigator and Distinguished Director of the VARI/SIMM Research Center in Shanghai, China. From left: Grant, Kang, Pal, Reynolds, Kovach, Powell, Xu, Ke, Sridharamurthy, Duan, Li, J. Chen, de Waal, Q. Chen, Zhi, Gu, Gao, Wang, Zhou Staff Students Visiting Scientists Xiang Gao, Ph.D. Stephanie Grant, B.S. Xin Gu, M.S. Yanyong Kang, Ph.D. Jiyuan Ke, Ph.D. Amanda Kovach, B.S. Kuntal Pal, Ph.D. Kelly Powell, B.S. Xiaoyong Zhi, Ph.D. Xiaoyin (Edward) Zhou, Ph.D. Christian Cavacece Parker de Waal, B.S. Xiaodan Li, B.S. Madhuri Sridharamurthy, B.S. Eileen Tan, B.S. Lili Wang, B.S. Feng Zhang, B.S. Jian Chen, Ph.D. Qin Chen, M.S. Xiaoqun Duan, Ph.D. Ross Reynolds, Ph.D. 40

Xu Research Interests Hormone signaling is essential to eukaryotic life. Our research is focused on the signaling mechanisms of physiologically important hormones, striving to answer fundamental questions that have a broad impact on human health and disease. The overall goals of the research program are to seek new biological paradigms through structural and functional analysis of key hormone signaling complexes and to develop therapeutic applications using the structural information we obtain. We currently focus on two families of proteins, the nuclear hormone receptors and the G protein–coupled receptors, because these proteins, beyond their fundamental roles in biology, are important drug targets for treating major human diseases. Nuclear hormone receptors Nuclear hormone receptors are a large family comprising ligand-regulated and DNA-binding transcription factors, which include 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. One distinguishing fact about these classic receptors is that they 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. Nuclear receptors also include a class of “orphan” receptors for which no ligand has been identified. 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 (PPAR, , and γ) are the 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 novel PPARγ 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 drugs called fibrates, and the new generation of anti-diabetic drugs, the glitazones. We have also determined the crystal structures of the receptors bound to coactivators or co-repressors and the crystal structure of PPARγ bound to a nitrated fatty acid. These structures have provided a framework for understanding the mechanisms of agonists and antagonists, as well as the recruitment of co-activators and corepressors in gene activation and repression. Furthermore, these structures serve as a molecular basis for understanding the potency, selectivity, and binding mode of diverse ligands and have provided crucial insights for designing the next generation of PPAR medicines. We have discovered a number of natural ligands of PPARγ. Our plan is to test their physiological roles in glucose and insulin regulation in order to unravel their molecular and structural mechanisms of action and to develop them into therapeutics for diabetes and dislipidemia. The human glucocorticoid receptor The human glucocorticoid receptor (GR), the prototype steroid hormone receptor, is crucial for a wide spectrum of human physiology including immune/inflammatory responses, metabolic homeostasis, and control of blood pressure. GR is a wellestablished target for drugs, and those drugs have an annual market of over billion. GR ligands such as dexamethasone and fluticasone propionate are used to treat asthma, leukemia, and autoimmune diseases. However, the clinical use of these ligands is limited by undesirable side effects partly associated with their receptor cross-reactivity or low potency. The discovery of potent and more-selective GR ligands—so-called “dissociated glucocorticoids” that have the potential to separate the good effects from the bad—remains a major goal of pharmaceutical research. We have determined a number of GR crystal structures bound to unique ligands and have found an unexpected regulatory mechanism: degradation by lysosomes. We also are studying the molecular and structural mechanisms of the dissociated glucocorticoids identified by our research. 41

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