The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the mechanism of macromolecular recognition and post-translational histone and protein modifications in the regulation of gene expression. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule compounds to treat such diseases.
| Post-translational histone modification for gene regulation |
| Histones package eukaryotic DNA into chromatin and are post-translationally modified to regulate gene expression in specific ways. We are studying the mechanism of action of these enzymes with a particular focus in histone acetyltransferases (HATs), deacetylases (HDACs) and kinases. We have determined the structures of various liganded forms of these enzymes and have carried out biochemical and enzymatic analysis to derive mechanistic details. We are continuing to probe the substrate specificity of these proteins and designing and characterizing inhibitors and are also characterizing relevant multiprotein enzyme complexes. We are also carrying out structural and biochemical studies on non-catalytic chromatin regulatory proteins, such as DNA-binding proteins, histone chaperones and chromatin targeting proteins. |
| Enzymes associated with aging and age-related disorders |
| Sirtuin enzymes are NAD+-dependent histone and protein deactylases and/or ADP-ribotransferases that have been implicated in the regulation of gene expression, cellular aging, adipogenesis, type II diabetes and several neurodegenerative disorders. We have determined the structure of these enzymes in several liganded forms. Together with associated biochemical studies, these studies have provided insights into the mode of catalysis and substrate-specific recognition by this protein family. We are currently using our structure-function information to design Sir2 regulatory compounds that might have therapeutic application. We are also pursuing structure/function studies of other enzymes that are implicated in aging and age-related disorders. |
| Tumor suppressors and oncoproteins |
We are carrying out biochemical and structural studies on the tumor suppressor proteins pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets. We are also interested in the mode of inactivation of these tumor suppressors by the viral oncoproteins E7 and E6 from human papillomavirus (HPV), the etiological agent for cervical cancer, and Adenovirus (Ad) E1A. We are also combining structural studies with small molecule screening to prepare inhibitors to HPV-E7 and HPV-E6. Most recently, we have begun to exploit structure-based design strategies to develop inhibitors of oncogenic kinases, such as PI3K and BRAF, implicated in melanoma and other cancers. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have clinical application.
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