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

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, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro () and Joong Myung Cho ()
Additional contact information
Byung-Je Sung: CrystalGenomics, Inc., Daedeok Biocommunity
Kwang Yeon Hwang: CrystalGenomics, Inc., Daedeok Biocommunity
Young Ho Jeon: CrystalGenomics, Inc., Daedeok Biocommunity
Jae Il Lee: CrystalGenomics, Inc., Daedeok Biocommunity
Yong-Seok Heo: CrystalGenomics, Inc., Daedeok Biocommunity
Jin Hwan Kim: CrystalGenomics, Inc., Daedeok Biocommunity
Jinho Moon: CrystalGenomics, Inc., Daedeok Biocommunity
Jung Min Yoon: CrystalGenomics, Inc., Daedeok Biocommunity
Young-Lan Hyun: CrystalGenomics, Inc., Daedeok Biocommunity
Eunmi Kim: CrystalGenomics, Inc., Daedeok Biocommunity
Sung Jin Eum: CrystalGenomics, Inc., Daedeok Biocommunity
Sam-Yong Park: Yokohama City University
Jie-Oh Lee: Korea Advanced Institute of Science and Technology
Tae Gyu Lee: CrystalGenomics, Inc., Daedeok Biocommunity
Seonggu Ro: CrystalGenomics, Inc., Daedeok Biocommunity
Joong Myung Cho: CrystalGenomics, Inc., Daedeok Biocommunity

Nature, 2003, vol. 425, issue 6953, 98-102

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01914

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