Module 5: Figure PDE5 functional states
A model depicting different functional states of PDE5.
PDE5 functions as a dimer with the two subunits connected through a region that includes the allosteric cyclic GMP-binding GAF domains. During the course of enzyme activation, cyclic GMP appears to bind first to the catalytic site (Km of 1–6 μM), which induces a conformational change that then enhances the affinity of cyclic GMP binding to the GAF domains. This binding to the regulatory region induces a further conformational change to expose the serine residue, which is then phosphorylated by cyclic GMP-dependent protein kinase (cGK). This phosphorylated state is the most active form of the enzyme. This thus represents a complex feedback loop whereby cyclic GMP promotes its own hydrolysis by binding allosterically to the enzyme and by promoting its phosphorylation by stimulating cGK. Reproduced from Handbook of Cell Signaling, Vol. 2, Francis, S.H. and Corbin, J.D., Phosphodiesterase-5, pp. 447–451. Copyright (2003), with permission from Elsevier; see Francis and Corbin 2003.