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

Nature volume 425, pages 98–102 (2003)Cite this article

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.

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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.

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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..

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Author notes

  1. Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon and Jae Il Lee: These authors contributed equally to this work

Authors and Affiliations

  1. The Division of Drug Discovery, CrystalGenomics, Inc., Daedeok Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon, 305-390, South Korea

    Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho

  2. Protein Design Laboratory, Yokohama City University, 1-7-29 Suehiro-cho, 230-0045, Tsurumi, Yokohama, Japan

    Sam-Yong Park

  3. Department of Chemistry, Korea Advanced Institute of Science and Technology, 373-1 Kusong-dong, Yuseong-gu, Daejeon, 305-701, South Korea

    Jie-Oh Lee

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Correspondence to Seonggu Ro or Joong Myung Cho.

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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

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