Abstract
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
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Beavo, J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75, 725–748 (1995)
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)
Corbin, J. D. & Francis, S. H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274, 13729–13732 (1999)
Rotella, D. P. Phosphodiestease 5 inhibitors: current status and potential applications. Nature Rev. Drug Discov. 1, 674–682 (2002)
Conti, M., Nemoz, G., Sette, C. & Vicini, E. Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr. Rev. 16, 370–389 (1995)
Torphy, T. J. Phosphodiesterase isozymes. Am. J. Respir. Crit. Care Med. 157, 351–370 (1998)
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)
Xu, R. X. et al. Atomic structure of PDE4: Insights into phosphodiesterase mechanism and specificity. Science 288, 1822–1825 (2000)
Lee, M. E., Markowitz, J., Lee, J.-O. & Lee, H. Crystal structure of phosphodiesterase 4D and inhibitor complex. FEBS Lett. 530, 53–58 (2002)
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)
Corbin, J. D. & Francis, S. H. Pharmacology of phosphodiesterase-5 inhibitors. Int. J. Clin. Pract. 56, 453–459 (2002)
Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995)
Nikolov, D. B. et al. Crystal structure of a TFIIB-TBP-TATA-element ternary complex. Nature 377, 119–128 (1995)
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)
Young, J. M. Expert opinion: Vardenafil. Expert Opin. Invest. Drugs 11, 1487–1496 (2002)
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)
Doublie, S. Preparation of selenomethionyl proteins for phase determination. Methods Enzymol. 276, 523–529 (1997)
Orme, M. W., Sawyer, J. S. & Schultze, L. M. Indole derivatives as PDE5-inhibitors. PCT Int. Appl. WO0236593 A1 (2002).
Otwinowski, M. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)
Terwilliger, T. C. & Berendzen, J. Automated MAD and MIR structure solution. Acta Crystallogr. D 55, 849–861 (1999)
Terwilliger, T. C. Maximum likelihood density modification. Acta Crystallogr. D 56, 965–972 (2000)
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)
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)
Acknowledgements
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
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights 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). https://doi.org/10.1038/nature01914
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01914
This article is cited by
-
Three-dimensional models of Mycobacterium tuberculosis proteins Rv1555, Rv1554 and their docking analyses with sildenafil, tadalafil, vardenafil drugs, suggest interference with quinol binding likely to affect protein’s function
BMC Structural Biology (2018)
-
In Silico Investigations of Chemical Constituents of Clerodendrum colebrookianum in the Anti-Hypertensive Drug Targets: ROCK, ACE, and PDE5
Interdisciplinary Sciences: Computational Life Sciences (2018)
-
Use of the KlADH3 promoter for the quantitative production of the murine PDE5A isoforms in the yeast Kluyveromyces lactis
Microbial Cell Factories (2017)
-
Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
Neuropsychopharmacology (2016)
-
Ultrafast protein structure-based virtual screening with Panther
Journal of Computer-Aided Molecular Design (2015)
Comments
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.