Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules


Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP1,2,3. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction4,5,6,7. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available8,9. Here we present the three-dimensional structures of the catalytic domain (residues 537–860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.

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

Access options

Buy this article

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

Figure 1: Overview of the PDE5 complex structures.
Figure 3: Comparison of PDE5 and PDE4 active sites.
Figure 2: Stereo view of the active site of the PDE5–sildenafil complex.

Similar content being viewed by others


  1. Beavo, J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75, 725–748 (1995)

    Article  CAS  Google Scholar 

  2. Soderling, S. H. & Beavo, J. A. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr. Opin. Cell Biol. 12, 174–179 (2000)

    Article  CAS  Google Scholar 

  3. Corbin, J. D. & Francis, S. H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274, 13729–13732 (1999)

    Article  CAS  Google Scholar 

  4. Rotella, D. P. Phosphodiestease 5 inhibitors: current status and potential applications. Nature Rev. Drug Discov. 1, 674–682 (2002)

    Article  CAS  Google Scholar 

  5. Conti, M., Nemoz, G., Sette, C. & Vicini, E. Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr. Rev. 16, 370–389 (1995)

    Article  CAS  Google Scholar 

  6. Torphy, T. J. Phosphodiesterase isozymes. Am. J. Respir. Crit. Care Med. 157, 351–370 (1998)

    Article  CAS  Google Scholar 

  7. Mehats, C., Andersen, C. B., Filopanti, M., Jin, S. L. & Conti, M. Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocr. Met. 13, 29–35 (2002)

    Article  CAS  Google Scholar 

  8. Xu, R. X. et al. Atomic structure of PDE4: Insights into phosphodiesterase mechanism and specificity. Science 288, 1822–1825 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Lee, M. E., Markowitz, J., Lee, J.-O. & Lee, H. Crystal structure of phosphodiesterase 4D and inhibitor complex. FEBS Lett. 530, 53–58 (2002)

    Article  CAS  Google Scholar 

  10. Rybalkin, S. D., Rybalkina, I. G., Shimizu-Albergine, M., Tang, X. B. & Beavo, J. A. PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J. 23, 469–478 (2003)

    Article  Google Scholar 

  11. Corbin, J. D. & Francis, S. H. Pharmacology of phosphodiesterase-5 inhibitors. Int. J. Clin. Pract. 56, 453–459 (2002)

    CAS  PubMed  Google Scholar 

  12. Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995)

    Article  ADS  CAS  Google Scholar 

  13. Nikolov, D. B. et al. Crystal structure of a TFIIB-TBP-TATA-element ternary complex. Nature 377, 119–128 (1995)

    Article  ADS  CAS  Google Scholar 

  14. Turko, I. V., Francis, S. H. & Corbin, J. D. Potential roles of conserved amino acids in the catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J. Biol. Chem. 273, 6460–6466 (1998)

    Article  CAS  Google Scholar 

  15. Young, J. M. Expert opinion: Vardenafil. Expert Opin. Invest. Drugs 11, 1487–1496 (2002)

    Article  CAS  Google Scholar 

  16. Sekhar, K. R., Grondin, P., Francis, S. H. & Corbin, J. D. Phosphodiesterase Inhibitors (eds Schudt, C., Dent, G. & Rabe, K. F.) 135–146 (Academic, New York, 1996)

    Book  Google Scholar 

  17. Doublie, S. Preparation of selenomethionyl proteins for phase determination. Methods Enzymol. 276, 523–529 (1997)

    Article  CAS  Google Scholar 

  18. Orme, M. W., Sawyer, J. S. & Schultze, L. M. Indole derivatives as PDE5-inhibitors. PCT Int. Appl. WO0236593 A1 (2002).

  19. Otwinowski, M. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  20. Terwilliger, T. C. & Berendzen, J. Automated MAD and MIR structure solution. Acta Crystallogr. D 55, 849–861 (1999)

    Article  CAS  Google Scholar 

  21. Terwilliger, T. C. Maximum likelihood density modification. Acta Crystallogr. D 56, 965–972 (2000)

    Article  CAS  Google Scholar 

  22. Jones, T., Zou, J.-Y., Cowan, S. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  Google Scholar 

  23. Brûnger, A. T. et al. Crystallography & N.M.R. system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  Google Scholar 

Download references


We are grateful to J. R. H. Tame for a critical reading of the manuscript. We thank Z. No for providing sildenafil citrate; D.-K. Kim for providing vardenafil; D. K. Shin for discussion and figures; and H.-S. Lee and G.-H. Kim for their assistance at the Pohang Light Source (PLS), beamline 6B. Experiments at PLS were supported, in part, by the Ministry of Science and Technology (MOST) of Korea and POSCO. We also thank S.Y.P's group for their assistance at Spring-8 for high-resolution data. This work was supported partially by a grant from the National Research Laboratory Program and the Center for Biological Modulators of the 21c Frontier R&D Program, subsidized MOST. This work was also supported partly by Yuyu Inc. and KT&G Co. Ltd..

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Seonggu Ro or Joong Myung Cho.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sung, BJ., Yeon Hwang, K., Ho Jeon, Y. et al. Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425, 98–102 (2003).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing