ABSTRACT
The molecular basis for the kinetic heterogeneity of 3',5'-cyclic guanosine monophosphate (cGMP) binding in Phosphodiesterase 5 (PDE5) is not understood, but the heterogeneity is likely to be related to conformational differences either among PDE5 dimers or between monomers within a given dimer. PDE5, like other PDEs, requires divalent cations for catalytic function and perhaps for maintaining catalytic site structure. PDE5 is subjected to long-term, developmental, and rapid onset regulation by a variety of biological processes. The stoichiometry of allosteric cGMP binding for either PDE5 holoenzyme or isolated R domain is ~0.6–0.8 mol/monomer. GAF-A binds cGMP with high affinity and may account entirely for PDE5 allosteric cGMP binding. Each x-ray crystal structure of the PDE5 C domain has significantly advanced understanding of the topography of the PDE5 catalytic site, identified ligand interactions, and provided important new information. Cyclic GMP binding to the allosteric sites in the PDE5 R domain increases catalytic activity.
