A molecular view of the regulation of sGC activity

Mammalian sGC is a heterodimer composed of and subunits (Figure 1). The C-terminus of each subunit contains a catalytic domain and the active site is composed of residues from both subunits. The catalytic domains also form a pseudosymmetric active site that contains residues known to be involved in nucleotide binding, but lack the amino acids required for catalysis. Sequence analysis shows that each subunit also contains well-defined PASlike domain, and a predicted helical region. The N-termini of the and -subunits are homologous to the H-NOX (Heme-Nitric oxide/OXygen) family of proteins. The Nterminus of -subunit contains a ferrous heme cofactor that serves a receptor for NO. sGC activity is also modulated by ATP and the substrate GTP and recent studies point toward a more complicated role for NO in the regulation of activity. Structural results coupled with biochemical and cellular experiments have broadened the current molecular view of the regulation of sGC. from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications Regensburg, Germany. 19–21 June 2009