In the past 20 years, RGS proteins have emerged as novel drug targets in numerous disease states, such as hypertension, cancer and Parkinson’s disease among others. This is not surprising given that 40-60% of currently FDA approved drugs target GPCR signaling. RGS protein levels and activity are tightly regulated in space and time by post-translational modifications, as well as transcriptional and epigenetic regulation and proteasomal degradation. Furtermore, several RGS proteins are down-regulated in disease states, leading to dysregulated GPCR signaling. Work in our lab aims to identify mechanisms by which RGS protein levels and activity are controlled and developing strategies to target these in drug discovery efforts. Enhancing RGS protein activity leads to suppression of GPCR signaling in a manner that is dependent on receptor activity. Thus, modulating RGS proteins would not create signals in the cells, rather modulating and fine-tuning signals occurring through the receptor.
RGS proteins all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. Many efforts have been made to develop inhibitors of the Gα-RGS interaction. Our lab instead focuses on finding strategies to enhance RGS protein function through modulation of the mechanisms that control activity and/or expression.
RGS proteins all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. Many efforts have been made to develop inhibitors of the Gα-RGS interaction. Our lab instead focuses on finding strategies to enhance RGS protein function through modulation of the mechanisms that control activity and/or expression.
Mechanisms of RGS2 protein degradation
More coming soon!
Development of small molecule RGS2 protein stabilizers
More coming soon!
Drug discovery for RGS10 protein enhancement
More coming soon!
