Abstract 2323: Molecular modeling studies of the STAT3 homodimer:DNA complex

Abstract Signal Transducers and Activators of Transcription (STAT) are a group of latent cytoplasmic transcription factors in cytokine signaling, that transduce signals from the cell membrane to the nucleus, where they activate gene transcription. STAT activation by phosphorylation is mediated by growth factors or cytokines, inducing STAT:STAT dimer formation between two monomers via reciprocal phosphoTyr formation. A member of the STAT family, STAT3 (Figure 1), has been found to be expressed at elevated levels in a large number of diverse human cancers, thus STAT3 represents a validated target for anticancer drug design. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent, unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. The results of molecular dynamics (MD) simulations of the activated STAT3 homodimer:DNA complex, and latent unphosporylated STAT3 monomer in explicit water have been studied. Careful analysis of the data obtained from MD simulations over a 35 ns time-frame has revealed the dynamics of the macromolecular complex at the atomistic level; how the transcription factor interacts with the DNA, the nature of the conformational changes, and the way function may be affected. Further analysis of the dimer interface, with a main focus on the protein-DNA interaction, including the water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. Moreover, locations of the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. In particular, we have been able to map out these mutations in detail and relate them to specific protein-DNA contacts. Their structural stability and importance will be described, along with a discussion of how this model is being used to assist in the discovery of novel small-molecule inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2323. doi:10.1158/1538-7445.AM2011-2323