Characterizing HMGA Binding to DNA and Inhibition by Small Molecules

HMGA (High Mobility Group Protein A) proteins are a family of nuclear proteins that bind AT rich DNA. These proteins are crucial during development and certain immune responses; however, their upregulation is linked to the spread of cancer. Unfortunately, the presence of HMGA1 (a subfamily of HMGA) is diagnostic of metastasis and poor prognosis for the patient. Therefore, downregulation of the DNA binding activity may allow for the development of novel therapeutics. However, these proteins are intrinsically disordered and they utilize two or three AT hook motifs to bind DNA in a cooperatively manner, making this family of proteins difficult to target. Our lab is developing a molecular understanding of how to target and disrupt these DNA binding proteins. In addition, we are studying how naturally occurring variations in the consensus AT hook sequence alters motif structure and DNA affinity.