Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Implications of PDE4 structure on inhibitor selectivity across PDE families

International Journal of Impotence Research volume 16, pages S24–S27 (2004)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Xu RX et al. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science 2000; 288: 1822–1825.

    Article  CAS  Google Scholar 

  2. Huai Q et al. Three dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure 2003; 11: 865–873.

    Article  CAS  Google Scholar 

  3. Vallee BL, Auld DS . Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 1990; 29: 5647–5659.

    Article  CAS  Google Scholar 

  4. Wilcox DE . Binuclear metallohydrolases. Chem Rev 1996; 96: 2435–2458.

    Article  CAS  Google Scholar 

  5. Hardman JG et al. The formation and metabolism of cyclic GMP. Ann NY Acad Sci 1971; 185: 27–35.

    Article  CAS  Google Scholar 

  6. Percival MD, Yeh B, Falgueyret JP . Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A). Biochem Biophys Res Commun 1997; 241: 175–180.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    CAS  PubMed  Google Scholar 

  10. Huai Q, Colicelli J, Ke H . The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis. Biochemistry 2003; 42: 13220–13226.

    Article  CAS  Google Scholar 

  11. Huang Z, Ducharme Y, Macdonald D, Robichaud A . The next generation of PDE4 inhibitors. Curr Opin Chem Biol 2001; 5: 432–438.

    Article  CAS  Google Scholar 

  12. Rotella DP . Phosphodiesterase 5 inhibitors: Current status and potential applications. Nat Rev Drug Discov 2002; 1: 674–682.

    Article  CAS  Google Scholar 

  13. Dym O, Xenarios I, Ke H, Colicelli J . Molecular docking of competitive phosphodiesterase inhibitors. Mol Pharmacol 2002; 61: 20–25.

    Article  CAS  Google Scholar 

  14. Lee ME, Markowitz J, Lee JO, Lee H . Crystal structure of phosphodiesterase 4D and inhibitor complex (1). FEBS Lett 2002; 530: 53–58.

    Article  CAS  Google Scholar 

  15. 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.

    CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    H Ke

Authors
  1. H Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Ke.

Rights and permissions

Reprints 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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijir.3901211

Keywords

  • phosphodiesterase inhibitors
  • PDE4
  • sildenafil
  • rolipram
  • 3′,5′-cyclic-nucleotide phosphodiesterase
  • protein conformation
  • binding sites

This article is cited by

Search

Advanced search

Quick links