Heptahelical receptors activate heterotrimeric G proteins by catalyzing exchange of GDP (bound to G"subunits) for GTP. G proteins are inactivated by intrinsic hydrolysis of GTP to GDP. This reaction is accelerated (for Gm and Gq> proteins) by several newly discovered RGS proteins. One such protein, RGS4, binds with highest affinity to the GDP-A1F4 -bound forms of G" proteins -conformations that mimic the transition state for GTP hydrolysis. The crystal structure of an RGS4/GDP-AlF4'-Gi0| complex (solved by J. Tesmer and S.R. Sprang, UT Southwestern) demonstrates interactions between the conserved core of RGS4 (a four-helix bundle) and the three mobile switch regions of Gial. RGS proteins thus appear to stabilize the transition state for nucleotide hydrolysis and may not themselves contribute functional residues to the active site. Adenylyl cyclase activity is controlled by regulation of the interaction between two homologous 25-kDa cytosolic domains of the enzyme. This interaction is stabilized synergistically by Gsa and forskolin. The heterodimeric complex formed by these engineered proteins contains one binding site for ATP (presumably at the domain interface), Gs", and forskolin. So-called P site inhibitors bind to the enzyme in concert with pyrophosphate. presumably to an altered conformation of the substrate binding site.
|Original language||English (US)|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas
- Molecular Biology