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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report The human androgen receptor The androgen receptor (AR) is the central molecule in the development and progression of prostate cancer. Mutations of the AR can alter the three-dimensional structure of the receptor in cancer cells and allow the cells to escape the repression of anti-androgen treatment. In this project, we intend to determine the structural basis of the mutant AR proteins. We have discovered that AR mutation in prostate cancers often results in enhanced binding to a particular coactivator, SRC-3 (which is also called “amplified in breast cancer 1”, or AIB1). We plan to study the structural and molecular mechanism of AR antagonists used in prostate cancer treatment and to determine a crystal structure of full-length AR bound to DNA and coactivator motifs. Structural genomics of nuclear receptor ligand-binding domains The LBDs of nuclear receptors contain key structural elements that mediate ligand-dependent regulation of nuclear receptors; as such, they have been the focus of intense structural study. In the past two years, we have focused on structural characterization of two orphan receptors: constitutive androstane receptor (CAR) and steroidogenic factor-1 (SF-1), and we have made significant progress in understanding their ligand binding relationships. In addition, we have identified retinoic acid as a low-affinity ligand for COUP-TF, which is one of the most conserved nuclear receptors and has essential roles in angiogenesis, heart development, CNS activity, and metabolic homeostasis. We plan to solve the structures of the remaining orphan receptors, of which there are only four left. The Met tyrosine kinase receptor The MET receptor is a tyrosine kinase that is activated by hepatocyte growth factor/scatter factor (HGF/SF). Aberrant activation of the Met receptor has been linked with development and metastasis of many types of solid tumors and has been correlated with poor clinical prognosis. In collaboration with George Vande Woude and Ermanno Gherardi, we plan to develop HGF-Met antagonists for treating solid tumors. G protein–coupled receptors GPCRs form the largest family of receptors in the human genome; they receive signals from photons, ions, small chemicals, peptides, and protein hormones. Although these receptors account for over 40% of drug targets, their structure remains 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. Currently my group is 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 and CRF receptors, 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 this system for expressing full-length GPCRs for crystallization and structure studies. From left, standing: Zhi, Jurecky, Holtrop, Pioszak, Guthrey, Powell, Kovach, Melcher, Parker, Bandyopadhyay, Zhang, E. Xu, Tolbert, Li, Ke, Ruivo kneeling: Malapaka, Y. Xu, Reynolds, Zhou, He 74

VARI | 2009 External Collaborators Eugene Chen and Doug Engel, University of Michigan, Ann Arbor Bruce Freeman, University of Pittsburgh School of Medicine, Pennsylvania Thomas J. Gardella, Massachusetts General Hospital and Harvard Medical School Ermanno Gherardi, University of Cambridge, London, United Kingdom Steve Kliewer and David Mangelsdorf, University of Texas Southwestern Medical Center, Dallas Dan R. Littman, New York University School of Medicine, New York Donald MacDonnell, Duke University, Durham, North Carolina Clay F. Semenkovich, Washington University, St. Louis, Missouri Stoney Simmons, National Institutes of Health, Bethesda, Maryland Scott Thacher, Orphagen Pharmaceuticals, San Diego, California Brad Thompson and Raj Kumar, University of Texas Medical Branch at Galveston Ming-Jer Tsai and Sophia Tsai, Baylor College of Medicine, Houston, Texas Jiemin Wong, Eastern China Normal University, Shanghai Eu Leong Yong, National University of Singapore Pfizer Pharmaceuticals Schering-Plough Pharmaceuticals Recent Publications Pioszak, Augen A., Naomi R. Parker, Thomas J. Gardella, and H. Eric Xu. 2009. Structural basis for parathyriod hormone–related protein binding to the parathyriod hormone receptor and design of conformation-selective peptides. Journal of Biological Chemistry 284(41): 28382–28391. Chakravarthy, Manu V., Irfan J. Lodhi, Li Yin, Raghu V. Malapaka, H. Eric Xu, John Turk, and Clay F. Semenkovich. 2009. Identification of a physiologically relevant endogenous ligand for PPARa in liver. Cell 138(3): 467–488. Knudsen, Beatrice S., Ping Zhao, James Resau, Sandra Cottingham, Ermanno Gherardi, Eric Xu, Bree Berghuis, Jennifer Daugherty, Tessa Grabinski, Jose Toro, et al. 2009. A novel multipurpose monoclonal antibody for evaluating human c-Met expression in preclinical and clinical settings. Applied Immunohistochemistry and Molecular Morphology 17(1): 56–67. Wang, Zhu, X. Edward Zhou, Daniel L. Motola, Xin Gao, Kelly Suino-Powell, Aoife Conneely, Craig Ogata, Kamalesh K. Sharma, Richard J. Auchus, James B. Lok, et al. 2009. Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proceedings of the National Academy of Sciences U.S.A.106(23): 9138–9143. Kruse, Schoen W., Kelly Suino-Powell, X. Edward Zhou, Jennifer E. Kretschman, Ross Reynolds, Clemens Vonrhein, Yong Xu, Liliang Wang, Sophia Y. Tsai, Ming-Jer Tsai, and H. Eric Xu. 2008. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid–activated receptor. PLoS Biology 6(9): e227. Li, Yong, Jifeng Zhang, Francisco J. Schopfer, Dariusz Martynowski, Minerva T. Garcia-Barrio, Amanda Kovach, Kelly Suino-Powell, Paul R.S. Baker, Bruce A. Freeman, Y. Eugene Chen, and H. Eric Xu. 2008. Molecular recognition of nitrated fatty acids by PPARg. Nature Structural & Molecular Biology 15(8): 865–867. 75

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