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; Joong Myung Cho

doi:10.1038/nature01914

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, Joong Myung Cho

Research output: Contribution to journal › Article › peer-review

253 Citations (Scopus)

Abstract

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. 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 dysfunction. 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 available. 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.

Original language	English
Pages (from-to)	98-102
Number of pages	5
Journal	Nature
Volume	425
Issue number	6953
DOIs	https://doi.org/10.1038/nature01914
Publication status	Published - 2003 Sept 4
Externally published	Yes

Bibliographical note

Funding Information:
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..

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nature01914

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@article{b8f2c6f46f164908a479ededcd982d1e,

title = "Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules",

abstract = "Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. 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 dysfunction. 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 available. 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.",

author = "Sung, {Byung Je} and Hwang, {Kwang Yeon} and Jeon, {Young Ho} and Lee, {Jae Il} and Heo, {Yong Seok} and Kim, {Jin Hwan} and Jinho Moon and Yoon, {Jung Min} and Hyun, {Young Lan} and Eunmi Kim and Eum, {Sung Jin} and Park, {Sam Yong} and Lee, {Jie Oh} and Lee, {Tae Gyu} and Seonggu Ro and Cho, {Joong Myung}",

note = "Funding Information: 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{\textquoteright}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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doi = "10.1038/nature01914",

language = "English",

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T1 - Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

AU - Sung, Byung Je

AU - Hwang, Kwang Yeon

AU - Jeon, Young Ho

AU - Lee, Jae Il

AU - Heo, Yong Seok

AU - Kim, Jin Hwan

AU - Moon, Jinho

AU - Yoon, Jung Min

AU - Hyun, Young Lan

AU - Kim, Eunmi

AU - Eum, Sung Jin

AU - Park, Sam Yong

AU - Lee, Jie Oh

AU - Lee, Tae Gyu

AU - Ro, Seonggu

AU - Cho, Joong Myung

N1 - Funding Information: 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..

PY - 2003/9/4

Y1 - 2003/9/4

N2 - Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. 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 dysfunction. 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 available. 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.

AB - Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. 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 dysfunction. 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 available. 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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U2 - 10.1038/nature01914

DO - 10.1038/nature01914

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AN - SCOPUS:0041321268

SN - 0028-0836

VL - 425

SP - 98

EP - 102

JO - Nature

JF - Nature

IS - 6953

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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