(A) The enzyme sGC contains two subunits, α and β, and each subunit is composed of four domains: the N-terminal heme nitric oxide/oxygen binding (HNOX) domain, the Per-Arnt-Sim (PAS) domain, the coiled-coil (CC) domain, and the catalytic domain. (B) In pulmonary arterial hypertension blood vessels contract excessively, thus increasing arterial pressure (left); this process can be reversed (blue arrow) by nitric oxide (NO, hexagons) and drugs called small sGC stimulators (triangles). These molecules bind to sGC and change its conformation so it becomes active and can catalyze the conversion of guanosine triphosphate (GTP, green hexagons) to cyclic guanosine monophosphate (cGMP, light green circles). This last molecule acts a secondary messenger and induces the dilation of blood vessels. Horst et al. have shed light on the mechanism of activation for the sGC enzyme. In the inactive state (bottom), the catalytic site is inaccessible, so the enzyme cannot catalyze the reaction that converts GTP to cGMP; there is also a sharp bend in each coiled-coil domain. When NO binds to the heme in the HNOX domain of the β subunit, the HNOX and PAS domains rotate by 71° leading to the straightening of the bend in the two coiled-coil domains, which opens the catalytic site, thus allowing the enzyme to catalyze the conversion of GTP to cGMP (top). Small stimulators such as YC-1 bind into the space created between the β HNOX and CC domains, acting as a wedge that keeps the enzyme active for longer.