Proteomimetic Strategy for the Modulation of Intrinsically Disordered Protein MYC

Abstract

The difficulty in developing specific ligands for protein receptors is directly correlated to the presence of unique binding sites on the protein surface. Conformationally dynamic proteins increase the level of difficulty in ligand design, and the challenge is further exacerbated for proteins that are intrinsically disordered. Intrinsically disordered proteins (or IDPs) do not adopt a fixed three-dimensional shape until they bind their target; an absence of organized binding sites underscores the difficulty in developing synthetic ligands for these proteins. We hypothesized that one avenue for the development of binders for a disordered region would be to trap one of its thermodynamically accessible conformations in a receptor. Here, we show the application of this approach to MYC, which represents a critical therapeutic target but has not yielded small-molecule inhibitors due to its conformationally dynamic nature. MYC adopts a helical configuration when it binds to its cellular partner MAX. We rationally designed a proteomimetic scaffold to trap this conformation. We show that MYC can be directly engaged in both biochemical and cellular assays. Overall, this work demonstrates a general method to capture and trap intrinsically disordered proteins with a propensity to adopt α-helical conformations.