STRUCTURE OF EWS-FLI1 AND HOW IT ATTACKS DNA
1. Project Background and Description
In Medicine, today, we treat the symptoms of most Cancers. We only provide cures in very few cases.
In order to provide more cures, we need to understand the root cause of the cancer of interest. Approximately 83% of Ewing Sarcomas exhibit reciprocal rearrangement of chromosomes 11 and 22 resulting in an EWSR1-FLI1 fusion protein. he N-terminus of EWSR1 and the C-terminus of FLI1 bind to transcriptional complexes and target genes, respectively. Therefore, the EWSR1-FLI1 fusion oncoprotein participates in Ewing sarcoma tumorigenesis by directly regulating target genes.
EWSR1-FLI1 binds with high affinity to sequences containing repetitive GGAA elements and regulates the expression of their target genes involved in oncogenic transformation in Ewing sarcoma. Schematically it looks like this:
We know that changes in cellular DNA are a primary cause of Cancer. However, the primary focus of most Cancer research is at the cell and tissue level. We need far better understanding of the molecular properties of DNA at the atomistic level to be able to actually CURE Cancer.
2. Project Scope
Our Research Objective will be to determine a structure for the EWS-FLI1 oncoprotein and characterize its binding to DNA.
3. High-Level Requirements
We will perform detailed, comparative modeling of the atomistic structure of the EWS-FLI1 oncoprotein from its established amino acid sequence to get an initial estimate of its structure. Further refinement will be achieved through Quantum Chemical and Molecular Mechanics calculations to determine a more detailed structure for the oncoprotein. Then we will use Quantum Chemical and Molecular dynamics methods to analyze the chemical reactivity.
A structure (or structures) for the EWS-FLI1 oncoprotein
Characterization of the chemical properties of the protein.
Static and dynamics analysis of the protein and its interactions with, and effect on, DNA.
Here is a view of a preliminary EWS-FLI1 structure we have determined using comparative modeling at the CαβS Protein Modeling Server: