Investigation of the PGC-1-alpha Co-activator Interacting with the Human Estrogen Receptor-alpha

The development of cancer in breast, thyroid, and uterine tissue is largely due to the uncontrolled expression of the estrogen receptor (ER). A well-founded understanding of the various factors and their interplay in the regulation of ER activity is imperative for the development of treatment and prevention strategies for these cancers. This research proposes to focus on the interactions between ER alpha and the co-activator PGC-1-alpha. The PGC-1-alpha actions are less sensitive towards the nature of the bound ligand in the ER, whereas classical co-activators interact with the ER in a highly ligand dependent fashion. Additionally, cases have been found where PGC-1-alpha interacts with ER in the absence of a ligand suggesting a binding mode, diverging from that of classical co-activators. Potential coactivator binding interfaces on the ligand binding domain (LBD), DNA binding domain (DBD), and hinge region of the ER alpha are of particular interest here. However, the tertiary structure of PGC-1-alpha is largely unknown. Homology modeling and tertiary structure prediction methods had to be applied to get reasonable and realistic tertiary structure predictions of PGC-1-alpha. Single point mutations and changes in rigidity of these interfaces as well as of the complementary interfaces on the co-activator are performed systematically. Interactions are simulated and analyzed, utilizing computational methods such as molecular dynamics, geometry optimization, and visualization. The resulting data should then provide insight into the possible binding modes of the PGC-1-alpha co-activator to the ER alpha. Furthermore, a basis will be established for future in vitro studies.