(500.18) Portability of Small Molecule Binding Sites in Intrinsically Disordered Proteins

Poster Board Number: A234

Ella Meyer (Georgetown University), Sachith DeSilva (Georgetown University), Steven Metallo (Georgetown University)

Intrinsically disordered proteins (IDPs) lack stable secondary and tertiary structure. Because they are associated with a range of diseases, IDPs are desirable therapeutic targets and have been targeted by small molecules. The transcription factor c-Myc (Myc) is an IDP that is implicated in over 70% of cancers. Previously, we have shown that several small molecules can bind to short, contiguous sequences on Myc. These sequences remain unstructured when binding to small molecules, potentially indicating only a limited dependence on residues outside of the contiguous binding residues. This mode of binding differs from that common in structured proteins where contact residues are often noncontiguous and scaffolded by extensive protein structure. Here we test the portability of a small molecule-IDP interaction implied by its dependence on only a short, linear sequence. We compare the binding of a small molecule to its specific recognition sequence in a native Myc context, in a minimalist peptide context, and by porting the binding sequence into the context of a different IDP. An ability of short, disordered sequences to bind small molecules in a context agnostic manner would have implications for the prediction and discovery of IDP binding sites broadly.