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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Structural genomics of nuclear 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 more than half of the 48 human nuclear receptors have been determined. These structures 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 regarding the identity of ligands, the size and shape of the ligand-binding pockets, and the structural implications of the 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. Our structures have helped to identify new ligands and signaling mechanisms for orphan nuclear receptors. G protein–coupled receptors (GPCRs) The GPCRs form the largest family of receptors in the human genome. They receive a diverse set of signals carried by photons, ions, small chemicals, peptides, and large protein hormones. These receptors 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 proteinprotein interactions. Currently we are focused on class B GPCRs, which includes receptors for parathyroid hormone (PTH), corticotropin-releasing 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. In addition, we are developing a mammalian overexpression system and plan to use it to express full-length GPCRs for crystallization and structural studies. Recent Publications Fu, T., S. Seok, S. Choi, Z. Huang, K. Suino-Powell, H.E. Xu, B. Kemper, and J.K. Kemper. In press. miR-34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte FGF21 signaling and SIRT1 function. Molecular and Cellular Biology. Li, X., L. Wang, E.X. Zhou, J. Ke, P.W. de Waal, X. Gu, M.H.E. Tan, D. Wang, D. Wu, H.E. Xu, et al. In press. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Research. He, Yuanzheng, Wei Yi, Kelly Suino-Powell, X. Edward Zhou, W. David Tolbert, Xiaobo Tang, Jing Yang, Huaiyu Yang, Jingjing Shi, et al. 2014. Structures and mechanism for the design of highly potent glucocorticoids. Cell Research 24(6): 713–726. Zhi, Xiaoyong, X. Edward Zhou, Yuanzheng He, Christoph Zechner, Kelly M. Suino-Powell, Steven A. Kliewer, Karsten Melcher, David J. Mangelsdorf, and H. Eric Xu. 2014. Structural insights into gene repression by the orphan nuclear receptor SHP. Proceedings of the National Academy of Sciences U.S.A. 111(2): 839–844. Chen, Chen, Jiyuan Ke, X. Edward Zhou, Wei Yi, Joseph S. Brunzelle, Jun Li, Eu-Leong Yong, H. Eric Xu, and Karsten Melcher. 2013. Structural basis for molecular recognition of folic acid by folate receptors. Nature 500(7463): 486–489. Wang, Chong, Yi Jiang, Jinming Ma, Huixian Wu, Daniel Wacker, Vsevolod Katritch, Gye Won Han, Wei Liu, Xi-Ping Huang, et al. 2013. Structural basis for molecular recognition at serotonin receptors. Science 340(6132): 610–614. 42

Tao Yang, Ph.D. Laboratory of Skeletal Biology Dr. Yang received his Ph.D. in biochemistry at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, in 2001. He then joined Baylor College of Medicine as a postdoctoral fellow, working with Paul Overbeek (2002–2004) and Brendan Lee (2004–2009). In 2009, he was appointed an instructor in the Department of Molecular and Human Genetics at Baylor. Dr. Yang joined VARI as an Assistant Professor in February 2013. Research Interests The skeletal system is the largest reservoir of mesenchymal stem cells (MSCs) in postnatal life. Large numbers of MSCs, in niches such as the marrow and periosteum, are necessary for the growth and maintenance of bone, which undergoes ceaseless remodeling and micro-damage repair. Dysregulations in MSC proliferation, lineage specification, and differentiation are common causes of skeletal fragility and of developmental or chronic diseases. Our long-term interest is to study how signals and cellular processes regulate MSC activity during skeletal development and homeostasis and how they affect skeletal disorders and aging. We have established in vivo genetics models and an ex vivo cell culture system that allow us to explore the mechanisms of AKT/ERK signaling integration in MSC renewal and differentiation, and the role of the sumoylation pathway in MSC renewal and senescence. Our studies could provide insights into the prevention or treatment of osteoporosis and osteoarthritis and into the healing and regeneration of skeletal tissues. Recent Publication Grafe, Ingo, Tao Yang, Stefanie Alexander, Erica P. Homan, Caressa Lietman, Ming Ming Jiang, Terry Bertin, Elda Munivez, Yuqing Chen, Brian Dawson, et al. 2014. Excessive transforming growth factor- signaling is a common mechanism in osteogenesis imperfecta. Nature Medicine 20(6): 670–675. From left: McMillan, Yang, Li, Lu, Lewis, Weaver Staff Diana Lewis, A.S. Jianshuang Li, B.S. Di Lu, M.S. Kevin Weaver, B.S. Student Adam McMillan 43

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