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PDBsum entry 1udu
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.
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Authors
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B.J.Sung,
K.Y.Hwang,
Y.H.Jeon,
J.I.Lee,
Y.S.Heo,
J.H.Kim,
J.Moon,
J.M.Yoon,
Y.L.Hyun,
E.Kim,
S.J.Eum,
S.Y.Park,
J.O.Lee,
T.G.Lee,
S.Ro,
J.M.Cho.
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Ref.
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Nature, 2003,
425,
98.
[DOI no: ]
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PubMed id
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Abstract
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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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Figure 2.
Figure 2: Stereo view of the active site of the PDE5 -sildenafil
complex. Sildenafil is shown as a stick model with carbon
atoms coloured yellow. Metal- and inhibitor-binding residues of
PDE5 are shown as stick models with carbon atoms coloured white.
The zinc (the bigger CPK model) and magnesium ions are shown in
orange and green, respectively. The amide moiety of the
pyrazolopyrimidinone group of sildenafil forms a bidentate
hydrogen bond with the  -amide
group of Gln 817, which is well ordered by a hydrogen bond relay
involving Gln 817 to Gln 775, Gln 775 to Ala 767 and Gln 775 to
Trp 853. The model orientation is the same as in Fig. 1a.
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Figure 3.
Figure 3: Comparison of PDE5 and PDE4 active sites. a,
Superimposed C  traces
of PDE5 (red) and PDE4 (blue)9 showing the difference between
the two folds at the active site. Residues 304 -325 of PDE5 and
660 -680 of PDE4D are shown with deeper colours to emphasize the
differences in this region. The stick model of sildenafil is
shown in yellow and that of zardaverine^9 in green. b, Surface
representation of active site pocket of PDE5. The molecular
surface is coloured according to electrostatic potential
(negative and positive in red and blue, respectively). Residues
that form the active site pocket are shown in green. The bound
sildenafil in PDE5 is shown as a stick model.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2003,
425,
98-0)
copyright 2003.
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