Enantiospecific Recognition of the Intrinsically Disordered C-Myc Oncoprotein by Small Molecules

Abstract

The prevalence of intrinsically disordered proteins (IDPs) in cell signaling and disease makes them attractive targets. Despite the absence of defined tertiary structure, small molecules can bind IDPs at sites determined by a short, linear segment of the protein's primary sequence. The oncoprotein c-Myc, a transcription factor that must undergo coupled folding and binding to its obligate partner Max in order to interact with DNA, is an attractive system for understanding specificity in small molecule binding to IDPs. Three independent small molecule binding sites exist in the bHLHZip region of c-Myc, the segment necessary for coupled folding and binding to Max. The chiral small molecule 10074-A4 recognizes one of these sites. A racemic mixture of 10074-A4 exhibits a circular dichroism signal upon binding to c-Myc indicating an enatioselective interaction of the molecule with the protein. We provide a model for this induced circular dichroism signal based on conformational selection in the binding enantiomer, and we synthesize the pure enantiomers and compare their binding. Derivatives of 10074-A4 were synthesized and these also display enatiospecific binding. Even though c-Myc is disordered, and remains so in the complex, it specifically recognizes both the chemical functionalities in the small molecule and their particular three dimensional arrangement.