3'5'-cyclic nucleotide phosphodiesterases (PDEases) catalyze the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates. There are at least seven different subfamilies of PDEases: Type 1, calmodulin/calcium-dependent PDEases. Type 2, cGMP-stimulated PDEases. Type 3, cGMP-inhibited PDEases. Type 4, cAMP-specific PDEases. Type 5, cGMP-specific PDEases. Type 6, rhodopsin-sensitive cGMP-specific PDEases. Type 7, High affinity cAMP-specific PDEases. All of these forms seem to share a conserved domain of about 270 residues. This entry has a signature pattern from a stretch of 12 residues that contains two conserved histidines. The PDEase catalytic domains adopt a compact alpha-helical structureconsisting of 16 alpha-helices that can be divided into three subdomains. The active site of PDEases is a deep pocket formed by the treesubdomains and can be divided into two major subpockets for binding ofdivalent metals and substrate/inhibitors, respectively. The active site of allPDEase domains contains two divalent metal ions: zinc and probably magnesium.