RGS proteins attenuate GPCR signals by increasing the GTPase activity of associated Gα proteins. Though they have been the focus of intense investigation as potential drug targets, the lack of suitable HTS assay methods has prevented large scale screening efforts. BellBrook overcame this technical hurdle by developing proprietary Gα variant proteins that enable direct detection of RGS catalytic activity using their Transcreener® HTS Assay platform.
The discovery of RGS proteins and their ability to attenuate GPCR signals opened up a new avenue for modulating the activity of GPCR ligands. The exploitation of this opportunity requires robust HTS assay methods. The most direct way to detect RGS function is by measuring the increased GTPase activity of the associated Gα protein. However, GTPase activity of isolated Gα proteins is limited by GDP dissociation, so RGS GAP activity cannot be measured using simple biochemical assays. The BellBrook team, collaborating with Dr. David Siderovski, a co-discoverer of the RGS protein family at the University of North Carolina - Chapel Hill School of Medicine, overcame this kinetic constraint
by creating Gα protein variants with altered GTP hydrolysis and GDP dissociation rates that enable detection of RGS GAP activity using the Transcreener® GDP Assay.
The innovative approach was described in a 2009 publication in the Journal of Biomolecular Screening. The RGScreen™ Assay Service provides custom assay development to produce and validate desired RGS protein targets followed by ongoing reagent supply, including RGS proteins, variant Gα proteins, and Transcreener® GDP Assay components, to support large scale RGS protein screening programs.