Mammalian adenylyl cyclases contain two conserved regions, C1 and C2, which are
responsible for forskolin- and G-protein-stimulated catalysis. The structure of
the C2 catalytic region of type II rat adenylyl cyclase has an alpha/beta class
fold in a wreath-like dimer, which has a central cleft. Two forskolin molecules
bind in hydrophobic pockets at the ends of cleft. The central part of the cleft
is lined by charged residues implicated in ATP binding. Forskolin appears to
activate adenylyl cyclase by promoting the assembly of the active dimer and by
direct interaction within the catalytic cleft. Other adenylyl cyclase regulators
act at the dimer interface or on a flexible C-terminal region.
