This project develops integrated computational and experimental approaches to inhibit a key protein-protein interaction between Regulators of G-protein Signaling (RGS) proteins and the α-subunits of heterotrimeric G-proteins. Inhibiting this interaction is significant in enhancing tissue-specific signaling via G-protein coupled receptors. The project is unique in developing allosteric targeting, as opposed to orthosteric targeting, as a novel approach for modulating protein-protein interfaces. Specifically, the project is aimed at a model RGS protein, RGS8, to delineate the role of each of the multiple inhibitor binding sites in achieving inhibitor selectivity for a specific RGS protein. Since some of the inhibitor binding sites are shared among RGS proteins, the approaches developed will be broadly applicable to other RGS isoforms.
