The mammalian PDEs share a common structural organization and contain three functional domains, which include the conserved catalytic core, a regulatory N-terminus, and the C-terminus. The conserved catalytic core is much more similar within PDE families, with about 80% amino acid identity, than between different families. It is believed that the core contains common structural elements that are important for the hydrolysis of cAMP and cGMP phosphodiester bonds. It is also believed that it contains family-specific determinants for differences in affinity for substrates and sensitivity for inhibitors.
The catalytic domain of PDE3 is characterized by a 44-amino acid insert, but this insert is unique to the PDE3 family, and is a factor when determining a structure for a potent and selective PDE3 inhibitor.
The crystal structure of the catalytic domains of several PDEs, including PDE3B, have shown that they contain three helical subdomains: 
# N-terminal cyclin fold region
# Linker region
# C-terminal helical bundle
At the interface of these domains a deep hydrophobic pocket is formed by residues that are highly conserved among all PDEs. This pocket is the active site and is composed of four subsites :
# Metal binding site (M site)
# Core pocket (Q pocket)
# Hydrophobic pocket (H pocket)
# Lid region (L region)
The M site is at the bottom of the hydrophobic binding pocket and contains two divalent metal binding sites. The metal ions that can bind to these sites are either zinc or magnesium. The zinc binding site has two histidine and two aspartic acid residues that are absolutely conserved among those PDEs studied to date.
The N-terminal portions of PDEs are widely divergent and contain determinants that are associated with regulatory properties specific to different gene families. For PDE3, those determinants are the hydrophobic membrane association domains and cAMP-dependent protein kinase phosphorylation sites.