2008 Scientific Report

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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, and as such it serves as the molecular target of anti-androgen therapy. However, most prostate cancer patients develop resistance to such therapy, mainly due to mutations in this hormone receptor that alter its three-dimensional structure and allow AR to escape repression. This hormone-independent cancer is highly aggressive and is responsible for most deaths from prostate cancer. In this project, we are aiming to determine the structures of mutated AR proteins that alter the response to anti-hormone therapy. In collaboration with Donald MacDonnell at Duke University, we are working on the crystal structure of the full-length AR/DNA complex. Orphan nuclear receptors We have focused on structural characterization of two orphan receptors: constitutive androstane receptor (CAR) and steroidogenic factor-1 (SF-1). The CAR structure reveals a compact LBD fold containing a small pocket that is only half the size of the pocket in PXR, a receptor closely related to CAR. The constitutive activity of CAR appears to be mediated by a novel linker helix between the C-terminal AF-2 helix and helix 10. On the other hand, SF-1 is regarded as a ligand-independent receptor, but its LBD structure reveals the presence of a phospholipid ligand in a surprisingly large pocket; more than twice the size of the pocket in the mouse LRH-1, a closely related receptor. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds formed with the phospholipid abolish the SF-1/coactivator interactions and reduce SF-1 transcriptional activity. These findings establish that SF-1 is a ligand-dependent receptor and suggest an unexpected link between nuclear receptors and phospholipid signaling pathways. The Met tyrosine kinase receptor MET is a tyrosine kinase receptor that is activated by hepatocyte growth factor/scatter factor (HGF/SF). Aberrant activation of the MET receptor has been linked to the development and metastasis of many types of solid tumors and correlates with poor clinical prognosis. HGF/SF has a modular structure with an N-terminal domain, four kringle domains, and an inactive serine protease domain. The structure of the N-terminal domain with a single kringle domain (NK1) has been determined. Less is known about the structure of the MET extracellular domain; thus, the molecular basis of the MET receptor–HGF/SF interaction and the activation of MET signaling by this interaction remains poorly understood. In collaboration with George Vande Woude and Ermanno Gherardi, we are developing this project to solve the crystal structure of the MET receptor/HGF complex. G protein–coupled receptors G protein–coupled receptors (GPCRs) form the largest family of receptors in the human genome; they are receptors for diverse signals carried by photons, ions, small chemicals, peptides, and hormones. These receptors account for over 40% of drug targets, but the structure of these receptors remains a challenge because they are seven-transmembrane molecules. Currently, there is only one reported GPCR structure, for an inactive form of bovine rhodopsin. From our standpoint, GPCRs are similar to nuclear hormone receptors with respect to regulation by protein-ligand and protein-protein interactions. Due to their importance, we have decided to take on studies of the structural basis of ligand binding in, and activation of, GPCRs. Currently, we are focusing on hormone recognition by Class B GPCRs, and we have recently determined the first structure of parathyroid hormone bound to the extracellular domain of its receptor. 78
VARI | 2008 External Collaborators Doug Engel, University of Michigan, Ann Arbor Ermanno Gherardi, University of Cambridge, United Kingdom Steve Kliewer, University of Texas Southwestern Medical Center, Dallas David Mangelsdorf, University of Texas Southwestern Medical Center, Dallas Donald MacDonnell, Duke University, Durham, North Carolina 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, Baylor College of Medicine, Houston, Texas From left, standing: Kruse, Chan, Zhou, Pioszak, Bandyopadhyay, Zhang, Zhong, Ke, Malapaka, Y. Xu, Melcher, Tolbert; seated: Guthrey, Parker, Conneely, Kovach, Powell, H.E. Xu Recent Publications Pioszak, Augen A., and H. Eric Xu. 2008. Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proceedings of the National Acadamy of Sciences U.S.A. 105(13): 5034–5039. Suino-Powell, Kelly, Yong Xu, Chenghai Zhang, Yong-guang Tao, W. David Tolbert, Stoney S. Simons, Jr., and H. Eric Xu. 2008. Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol. Molecular and Cellular Biology 28(6): 1915–1923. Guo, Dongsheng, Joy Sarkar, Kelly Suino-Powell, Yong Xu, Kojiro Matsumoto, Yuzhi Jia, Songtao Yu, Sonal Khare, Kasturi Haldar, M. Sambasiva Rao, Jennifer E. Foreman, Satdarshan P.S. Monga, Jeffrey M. Peters, H. Eric Xu, and Janardan K. Reddy. 2007. Induction of nuclear translocation of constituitive androstane receptor by peroxisome proliferator–activated receptor a synthetic ligands in mouse liver. Journal of Biological Chemistry 282(50): 36766–36776. Tolbert, W. David, Jennifer Daugherty, Chongfeng Gao, Qian Xie, Cindy Miranti, Ermanno Gherardi, George Vande Woude, and H. Eric Xu. 2007. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proceedings of the National Academy of Sciences U.S.A. 104(37): 14592–14597. 79
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2008 Scientific Report

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