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2016 Scientific Report

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and antagonists and the

and antagonists and the recruitment of co-activators and co-repressors in gene activation and repression. They also increase our understanding of the potency, selectivity, and binding mode of ligands and provide crucial insights for designing the next generation of PPAR medicines. We have discovered several natural ligands of PPARγ. Our plan is to test their physiological roles in glucose and insulin regulation and to develop them into therapeutics for diabetes and dislipidemia. The human glucocorticoid receptor The human glucocorticoid receptor (GR), the prototypical steroid hormone receptor, affects a wide spectrum of human physiology including immune/inflammatory responses, metabolic homeostasis, and control of blood pressure. GR is a well-established target for drugs, and those drugs have an annual market of over billion. However, the clinical use of GR ligands is limited by undesirable side effects partly resulting from receptor cross-reactivity or low potency. The discovery of potent, more-selective GR ligands— “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. Structural genomics of receptor LBDs The ligand-binding domain of a nuclear receptor contains key structural elements that mediate ligand-dependent regulation of the receptors and, as such, it has been the focus of intense structural studies. Crystal structures for most of the 48 human nuclear receptors have been determined and have illustrated the details of ligand binding, the conformational changes induced by agonists and antagonists, the basis of dimerization, and the mechanism of co-activator and co-repressor binding. The structures also have provided many surprises about the identity of ligands and their implications for receptor signaling pathways. There are only a few “orphan” nuclear receptors for which the LBD structure remains unsolved. In the past few years, we have determined the crystal structures of the LBDs of CAR, SHP, SF-1, COUP-TFII, and LRH-1, and our structures have helped to identify new ligands and signaling mechanisms for these orphan receptors. G protein–coupled receptors (GPCRs) The GPCRs form the largest family of receptors in the human genome and account for over 40% of drug targets, but their structures remain a challenge because they are seven-transmembrane receptors. There are only a few crystal structures for class A GPCRs, and many important questions regarding GPCR ligand binding and activation remain unanswered. From our standpoint, GPCRs are similar to nuclear hormone receptors with respect to regulation by protein-ligand and protein–protein interactions. We focus on class B GPCRs, which includes receptors for parathyroid hormone (PTH), corticotropinreleasing factor (CRF), glucagon, and glucagon-like peptide-1. We have determined crystal structures of the ligand-binding domain of the PTH receptor and the CRF receptor, and we are developing hormone analogs for treating osteoporosis, depression, and diabetes. We are developing a mammalian overexpression system and plan to use it to express full-length GPCRs for crystallization and structural studies. RECENT PUBLICATIONS He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015. Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035. Kang, Yanyong, X. Edward Zhou, Xiang Gao, Yuanzheng He, Wei Liu, Andrii Ishchenko, Anton Barty, Thomas A. White, Oleksandr Yefanov, et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523(7562): 561–567. 28 Van Andel Research Institute | Scientific Report

TAO YANG, PH.D. Dr. Yang received his Ph.D. in biochemistry at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, in 2001. He joined VARI as an Assistant Professor in February 2013. STAFF DIANA LEWIS, A.S. JIANSHUANG LI, B.S. JIE LI, PH.D. HUADIE LIU, M.S. DI LU, M.S. KEVIN WEAVER, B.S. RESEARCH INTERESTS The skeletal system develops from mesenchymal cells and is the major reservoir of mesenchymal stem cells (MSCs) in adult life. MSCs play pivotal roles in skeletal tissue growth, homeostasis, and repair, while dysregulations in MSC renewal, linage specification, and pool maintenance are common causes of skeletal disorders. Our long-term interest is to investigate the signals and cellular processes orchestrating the activities of MSCs and MSC-derived cells during skeletal development and homeostasis and how those processes are involved in skeletal aging and disorders. Our current projects in skeletal development and disease include a study of the sumoylation pathway and a study of LRP1 signaling. As part of these projects, we have established in vivo and in vitro genetic models to study the molecular mechanisms underlying osteoarthritis and osteoporosis. RECENT PUBLICATIONS Chen, Shan, Monica Grover, Tarek Sibai, Jennifer Black, Nahid Rianon, Abbhirami Rajagopal, Elda Munivez, Terry Bertin, Brian Dawson, et al. 2015. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton. Molecular Genetics and Metabolism 115(1): 53–60. He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015. Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035. Lu, Linchao, Karine Harutyunyan, Weidong Jin, Jianhong Wu, Tao Yang, Yuqing Chen, Kyu Sang Jeoeng, Yangjin Bae, Jianning Tao, et al. 2015. RECQL4 regulates p53 function in vivo during skeletogenesis. Journal of Bone and Mineral Research 30(6): 1077–1089. CENTER FOR CANCER AND CELL BIOLOGY 29

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