title: Implications of PDE4 structure on inhibitor selectivity across PDE families.
abstract: Phosphodiesterases (PDEs) control cellular concentrations of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). PDE4 and PDE5 selectively hydrolyze cAMP and cGMP, respectively. PDE family members share approximately 25% sequence identity within a conserved catalytic domain of about 300 amino acids. Crystal structure analysis of PDE4's catalytic domain identifies two metal-binding sites: a high-affinity site and a low-affinity site, which probably bind zinc (Zn2+) and magnesium (Mg2+), respectively. Absolute conservation among the PDEs of two histidine and two aspartic acid residues for divalent metal binding suggests the importance of these amino acids in catalysis. Although active sites of PDEs are apparently structurally similar, PDE4 is specifically inhibited by selective inhibitors such as rolipram, while PDE5 is preferentially blocked by sildenafil. Modeling interactions of the PDE5 inhibitor sildenafil with the PDE4 active site may help explain inhibitor selectivity and provide useful information for the design of new inhibitors.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ke
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D000068677:Sildenafil Citrate; D013379:Substrate Specificity; D013450:Sulfones; D015032:Zinc / Q000378:metabolism
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP; D008274:Magnesium; D015032:Zinc