Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits

Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by G alpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with G alpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of G alpha, RGS domain binding consequently accelerates G alpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied G alpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential G alpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/G alpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the G alpha substrate, suggests that unique structural determinants specific to particular RGS protein/G alpha pairings exist and could be used to achieve selective inhibition by small molecules.