This project presents integrated experimental and computational studies of mechanisms of recognition of novel small-molecule based therapeutics for targeting allosteric sites in intracellular signaling proteins of the G-protein coupled receptor family. The project is motivated by the fact that allosteric modulation is emerging as a unifying mechanism for the function as well as regulation of receptors. Therefore, targeting allosteric sites or pathways has the potential to modulate receptor activity and enhance drug-specificity. The proposed studies will involve experimental (Nuclear Magnetic Resonance spectroscopy; NMR) and computational (molecular dynamics; MD) studies aimed at resolving structural perturbations in RGS proteins on binding of inhibitors, with a long-term goal to obtain a high-resolution solution structure of an RGS protein bound to a covalently-linking inhibitor. Specifically, RGS8 will be studied as a model RGS isoform in combination with CCG-203769, a covalently linking aliphatic inhibitor, to map structural perturbations. Characterizing these perturbations will not only provide residue-specific insights into dynamics of RGS proteins on inhibitor binding, but also will be crucial to obtain the first high resolution solution structure of an RGS isoform when bound to an allosteric inhibitor.
