Our interests are focused on using X-ray crystal structural, molecular and biochemical multidisciplinary approaches to study the protein structure and function with emphasis on their implications on drug discovery and therapeutics. Nuclear receptors work as ligand inducible transcription factors and they are among the most successful drug targets in history. There are 48 nuclear receptors in human including classic steroid hormone receptors for estrogen, progesterone, androgens, and glucocorticoids, as well as receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. The nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) is expressed at highest level in adipose tissue and is a key transcription factor involved in adipocyte differentiation. Thiazolidinedione (TZD) ligands that bind and activate PPARgamma are currently used in the treatment of type 2 diabetes in humans. Moreover, PPARgamma also has been closely associated with cancer. To understand the molecular basis of ligand-mediated signaling of PPARgamma in cancer and diabetes, we are interested in determining X-ray crystal structures PPAR/ligand/cofactor complexes and defining the structure/function relationships. The functional implications of the key structural elements that affect the binding of ligand and coactivator are assessed using in vitro AlphaScreen assays and in vivo cell-based assays. This study will provide important insights into biological implications of the PPARgamma and their ligands on cancer and diabetes, and thus lead to structure-based drug design for highly selective and efficient forms for human therapeutics uses.

IXu, H.E and Li, Y. Ligand-dependent and -independent regulation of PPAR gamma and orphan nuclear receptors. Sci. Signal 1, pe52 (2008)

Li, Y., Zhang, J., Schopfer, F., Martynowski, D., Garcia-Barrio, M., Kovach, A., Suino-Powell, K., Baker, P., Freeman, B., Chen, Y., and Xu, H.E. Molecular recognition of nitro-fatty acids by PPAR?. Nature Structural & Molecular Biology 15:865-7 (2008)

Li, Y., Kovach, A., Suino-Powell, K., Martynowski, D., and Xu, H.E. Structural and Biochemical Basis for the Binding Selectivity of PPAR? to PGC1? . Journal of Biological Chemistry 283:19132-9 (2008)

Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., Elmquist, J.K., Gerard, R.D., Burgess, S.C., Hammer, R.E., Mangelsdorf D.J., and Kliewer, S.A. Endocrine regulation of the fasting response by PPAR_-mediated induction of fibroblast growth factor 21. Cell Metab 5:415-425 (2007)

Motola, D., Cummins, L., Rottiers, V., Sharma, K., Li, T., Li, Y., Powell, K., Xu, H.E., Auchus, R.J., Antebi, A., and Mangelsdorf, D.J. Identification of Ligands for DAF-12 that Govern Dauer Formation and Reproduction in C. elegans. Cell 124:1209-1223 (2006)

Li, Y., Suino, K., Daugherty, J., and Xu, H.E. Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Molecular Cell 19:367-80 (2005)

Li, Y., Choi, M., Suino, K., Kovach, A., Daugherty, J., Kliewer, S.A., and Xu, H.E. Structural and biochemical basis for selective repression of the orphan nuclear receptor LRH-1 by SHP. Proc Natl Acad Sci U S A. 102:9505-10 (2005)

Li, Y., Choi, M., Cavey, G., Daugherty, J., Suino, K., Kovach, A., Bingham, N.C., Kliewer, S.A., and Xu, H.E. Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Molecular Cell 17: 491-502. (2005)