Abstract
The intrinsic activity of the C-terminal catalytic (C) domain of cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKG) is inhibited by interactions with the N-terminal regulatory (R) domain. Selective binding of cGMP to cyclic nucleotide binding (CNB) domains within the R-domain disrupts the inhibitory R-C interaction, leading to the release and activation of the C-domain. Affinity measurements of mammalian and plasmodium PKG CNB domains reveal different degrees of cyclic nucleotide affinity and selectivity; the CNB domains adjacent to the C-domain are more cGMP selective and therefore critical for cGMP-dependent activation. Crystal structures of isolated CNB domains in the presence and absence of cyclic nucleotides reveal isozyme-specific contacts that explain cyclic nucleotide selectivity and conformational changes that accompany CNB. Crystal structures of tandem CNB domains identify two types of CNB-mediated dimeric contacts that indicate cGMP-driven reorganization of domain-domain interfaces that include large conformational changes. Here, we review the available structural and functional information of PKG CNB domains that further advance our understanding of cGMP mediated regulation and activation of PKG isozymes.