Disorderly Proteins Turn Predictable

Small-molecule-binding sites aren't just the hallmark of enzymes and receptors anymore. Chemists have found evidence that floppy, unstructured proteins contain regions prone to binding small molecules. The finding could lead to better tools for basic research on disordered proteins and may someday help researchers targeting such proteins in drug discovery.

Intrinsically disordered proteins play roles in gene transcription, cell division, and more, but researchers don't have a straightforward way of making molecules that alter their activity. Now, Dalia I. Hammoudeh, Ariele Viacava Follis, and Steven J. Metallo of Georgetown University, together with pediatric oncologist Edward V. Prochownik of the University of Pittsburgh Medical Center, have outlined a way to do just that (J. Am. Chem. Soc., DOI:10.1021/ja900616b). The findings might enable scientists to predict binding sites on disordered proteins and therefore screen for inhibitors more efficiently.

The team studied an 85-amino acid segment of a disordered protein called c-Myc, which is implicated in several cancers. Prochownik's group previously found seven structurally diverse small molecules that prevent c-Myc's interaction with a partner protein, thus blocking its activity. Now, with NMR and other spectroscopic techniques, the team has identified three peptide stretches on c-Myc that recognize all of those inhibitors. Each stretch is highly hydrophobic and contains a few amino acids that distinguish c-Myc from similar sites on related proteins, which helps in finding selective c-Myc inhibitors.

Because the new work has revealed three distinct small-molecule-binding sites on a short segment of one protein, it's likely that there are many similar sites throughout the proteome, Metallo says. "We believe that these clusters of hydrophobic residues are likely to be good places to look for small-molecule-binding sites in other disordered proteins as well," he adds.

Searches for inhibitors, such as in this study, have borne out bioinformatics predictions about the key roles unstructured proteins play in biology, says A. Keith Dunker, a theoretical biologist at Indiana University-Purdue University, Indianapolis. The team's insight "opens new vistas for altering cell behavior and for drug discovery," he adds.