The major research goal in Dr. Ladias' section is to determine the molecular mechanisms of transcriptional regulation of human gene expression in response to physiologic signals. Dr. Ladias' section aims at dissecting the molecular mechanisms of gene expression and to deriving structural information about the proteins that mediate this regulation. Investigators in this group use x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy to locate the three-dimensional position of all the atoms of a macromolecule. This information can be used to visualize and study the macromolecule, and to search existing structural databases for small organic compounds that might fit in its active site and alter its activity. These organic molecules then become the lead compounds for the synthesis of derivatives with higher potency and fewer side effects. Thus, the basic research conducted in Dr. Ladias' section is expected to produce important insights into gene regulation and, we hope, provide a basis for the rational design of clinically useful pharmaceuticals.
In parallel, the Ladias laboratory also studies the regulation of genes participating in cholesterol metabolism and diabetes, in response to signals transduced by members of the nuclear hormone receptor family of transcription factors.
Investigators in the Ladias laboratory are attempting to determine the three-dimensional structure of Rev complexed with its molecular targets RIP1 and Rev-binding element, using x-ray crystallography. These studies will provide new insights into the structure of the Rev protein at the atomic level, and will promote the generation of testable hypotheses about the function of Rev.
Recently, the Ladias laboratory has also focused on the modulation of RNA polymerase II function by the transactivating protein Tat of HIV-1, an essential regulator of viral replication. Crystallization studies and crystallographic analysis of this complex have been initiated.
For these studies, the Ladias section combines cutting-edge technologies in molecular biology, genetics, and structural biology. The x-ray crystallographic analyses are performed in the Macromolecular Crystallography Unit, a state-of-the-art facility in the Division. The NMR structural studies are pursued in collaboration with other groups.