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PDBsum entry 1q9m
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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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Three-Dimensional structures of pde4d in complex with roliprams and implication on inhibitor selectivity.
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Authors
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Q.Huai,
H.Wang,
Y.Sun,
H.Y.Kim,
Y.Liu,
H.Ke.
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Ref.
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Structure, 2003,
11,
865-873.
[DOI no: ]
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PubMed id
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Abstract
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Selective inhibitors against the 11 families of cyclic nucleotide
phosphodiesterases (PDEs) are used to treat various human diseases. How the
inhibitors selectively bind the conserved PDE catalytic domains is unknown. The
crystal structures of the PDE4D2 catalytic domain in complex with (R)- or
(R,S)-rolipram suggest that inhibitor selectivity is determined by the chemical
nature of amino acids and subtle conformational changes of the binding pockets.
The conformational states of Gln369 in PDE4D2 may play a key role in inhibitor
recognition. The corresponding Y329S mutation in PDE7 may lead to loss of the
hydrogen bonds between rolipram and Gln369 and is thus a possible reason
explaining PDE7's insensitivity to rolipram inhibition. Docking of the PDE5
inhibitor sildenafil into the PDE4 catalytic pocket further helps understand
inhibitor selectivity.
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Figure 6.
Figure 6. A Model for Insensitivity of PDE7 to Rolipram
Inhibition(A) The hydrogen bonds (dotted lines) between Gln369
and rolipram in PDE4.(B) The correspondence of residues Ser373,
Ser377, and Gln413 in PDE7A to Tyr329, Thr333, and Gln369 in
PDE4D2 may lead Gln413 to adopt a new conformation to form a
hydrogen bond with Ser377. As a result, Gln413 would not be
capable of forming hydrogen bonds with rolipram. The orange
sticks mark the side chain conformation of Gln369 in PDE4.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2003,
11,
865-873)
copyright 2003.
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