STRUCTURE OF THE ADENYLYL-CYCLASE CATALYTIC CORE

Mammalian adenylyl cyclases contain two conserved regions, C-1 and C-2 , which are responsible for forskolin- and G-protein-stimulated cataly sis. The structure of the C-2 catalytic region of type II rat adenylyl cyclase has an alpha/beta class fold in a wreath-like dimer, which ha s a central cleft. Two forskolin molecules bind in hydrophobic pockets at the ends of cleft. The central part of the cleft is lined by charg ed residues implicated in ATP binding. Forskolin appears to activate a denylyl cyclase by promoting the assembly of the active dimer and by d irect interaction within the catalytic cleft. Other adenylyl cyclase r egulators act at the dimer interface or on a flexible C-terminal regio n.