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 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.
Sung
Byung-Je
BJ
Division of Drug Discovery, CrystalGenomics, Inc., Daedeok Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon, 305-390, South Korea.
Hwang
Kwang Yeon
KY
Jeon
Young Ho
YH
Lee
J I
JI
Heo
Yong-Seok
YS
Kim
Jin Hwan
JH
Moon
Jinho
J
Yoon
Jung Min
JM
Hyun
Young-Lan
YL
Kim
Eunmi
E
Eum
Sung Jin
SJ
Park
Sam-Yong
SY
Lee
Jie-Oh
JO
Lee
Tae Gyu
TG
Ro
Seonggu
S
Cho
Joong Myung
JM
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001665:Binding Sites; D002243:Carbolines / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D000068581:Tadalafil; D014227:Triazines; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D007093:Imidazoles; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human