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.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 8 print issues and online access
$259.00 per year
only $32.38 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Xu RX et al. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science 2000; 288: 1822–1825.
Huai Q et al. Three dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure 2003; 11: 865–873.
Vallee BL, Auld DS . Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 1990; 29: 5647–5659.
Wilcox DE . Binuclear metallohydrolases. Chem Rev 1996; 96: 2435–2458.
Hardman JG et al. The formation and metabolism of cyclic GMP. Ann NY Acad Sci 1971; 185: 27–35.
Percival MD, Yeh B, Falgueyret JP . Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A). Biochem Biophys Res Commun 1997; 241: 175–180.
Callahan SM, Cornell NW, Dunlap PV . Purification and properties of periplasmic 3′,5′-cyclic nucleotide phosphodiesterase. A novel zinc-containing enzyme from the marine symbiotic bacterium Vibrio fischeri. J Biol Chem 1995; 270: 17627–17632.
Omburo GA, Jacobitz S, Torphy TJ, Colman RW . Critical role of conserved histidine pairs HNXXH and HDXXH in recombinant human phosphodiesterase 4A. Cell Signal 1998; 10: 491–497.
Francis SH, Colbran JL, McAllister-Lucas LM, Corbin JD . Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J Biol Chem 1994; 269: 22477–22480.
Huai Q, Colicelli J, Ke H . The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis. Biochemistry 2003; 42: 13220–13226.
Huang Z, Ducharme Y, Macdonald D, Robichaud A . The next generation of PDE4 inhibitors. Curr Opin Chem Biol 2001; 5: 432–438.
Rotella DP . Phosphodiesterase 5 inhibitors: Current status and potential applications. Nat Rev Drug Discov 2002; 1: 674–682.
Dym O, Xenarios I, Ke H, Colicelli J . Molecular docking of competitive phosphodiesterase inhibitors. Mol Pharmacol 2002; 61: 20–25.
Lee ME, Markowitz J, Lee JO, Lee H . Crystal structure of phosphodiesterase 4D and inhibitor complex (1). FEBS Lett 2002; 530: 53–58.
Underwood DC et al. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther 1994; 270: 250–259.
Saenz de Tejada I et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 2001; 13: 282–290.
Rights and permissions
About this article
Cite this article
Ke, H. Implications of PDE4 structure on inhibitor selectivity across PDE families. Int J Impot Res 16 (Suppl 1), S24–S27 (2004). https://doi.org/10.1038/sj.ijir.3901211
- phosphodiesterase inhibitors
- 3′,5′-cyclic-nucleotide phosphodiesterase
- protein conformation
- binding sites
This article is cited by
Synaptic Therapy in Alzheimer’s Disease: A CREB-centric Approach
Phosphodiesterase 4 Inhibition Impairs Cocaine-Induced Inhibitory Synaptic Plasticity and Conditioned Place Preference
The involvement of type IV phosphodiesterases in cocaine-induced sensitization and subsequent pERK expression in the mouse nucleus accumbens
Phosphodiesterase 4A, cAMP specific
AfCS-Nature Molecule Pages (2006)
Phosphodiesterase 4B, cAMP specific
AfCS-Nature Molecule Pages (2006)