The ETS transcription factor ERG is a master regulator of multiple vascular processes. Pathological dysregulation of endothelial ERG has been linked to inflammatory disorders. In non-endothelial cells, aberrant ectopic overexpression of ERG in cancer is oncogenic. Whilst many aspects of ERG’s biological and pathological role have been uncovered, the underlying molecular mechanisms are often not fully understood; likely impeded by the lack of a full-length crystal structure. I combined in silico Molecular Dynamics (MD) and in vitro assays to gain further insight into the functionality of ERG at the molecular level. A new ERG full-length structure was developed using MD. This model was used to study the structural basis for the binding specificity of ERG at DNA sequence variants of the ERG binding site. This identified key changes in ERG-DNA contacts depending on the binding motif. ERG activity can be modulated through posttranslational modifications including phosphorylation. Using the new ERG structural model, I gained a better understanding of the molecular consequences of ERG phosphorylation by ERK2. I found that upon Ser215 and Ser96 phosphorylation ERG undergoes conformational changes in the C- and N- termini, respectively. Using an electrophoresis mobility shift assay I showed that Ser215 phosphorylation increased the DNA binding of ERG. This goes in line with the in silico observed structural change in the C-terminus of ERG, where the DNA binding domain is located. Finally, I identified structural differences in the DNA binding ETS domain in an ERG variant found in a patient with primary lymphodoema. I showed changes in DNA binding, which was confirmed independently using in vitr oassays. Overall, the new structural modelwas successfully used to gain insight into the molecular mechanism underlying ERGactivity. Other aspects of ERG activity could be studied with the new model, potentially aiding the development of new therapeutic strategies.