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PDBsum entry 1ror
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the catalytic domain of phosphodiesterase 4b complexed with AMP, 8-Br-Amp, And rolipram.
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Authors
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R.X.Xu,
W.J.Rocque,
M.H.Lambert,
D.E.Vanderwall,
M.A.Luther,
R.T.Nolte.
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Ref.
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J Mol Biol, 2004,
337,
355-365.
[DOI no: ]
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PubMed id
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Abstract
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Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger
3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase
4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an
attractive target for the treatment of asthma and COPD. We have determined
crystal structures of the catalytic domain of PDE4B complexed with AMP (2.0 A),
8-Br-AMP (2.13 A) and the potent inhibitor rolipram (2.0 A). All the ligands
bind in the same hydrophobic pocket and can interact directly with the active
site metal ions. The identity of these metal ions was examined using X-ray
anomalous difference data. The structure of the AMP complex confirms the
location of the catalytic site and allowed us to speculate about the detailed
mechanism of catalysis. The high-resolution structures provided the experimental
insight into the nucleotide selectivity of phosphodiesterase. 8-Br-AMP binds in
the syn conformation to the enzyme and demonstrates an alternative
nucleotide-binding mode. Rolipram occupies much of the AMP-binding site and
forms two hydrogen bonds with Gln443 similar to the nucleotides.
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Figure 7.
Figure 7. Binding of 8-Br-AMP in the PDE4B active site. The
protein backbone is shown as a gray ribbon. The Br is colored
dark red. The carbon atoms of 8-Br-AMP are colored yellow, the
phosphate is colored pink. The carbon atoms of important
side-chain of the protein are shown in green. The metal ions are
shown as yellow balls. The hydrogen bonds between protein and
8-Br-AMP are shown as white dotted lines. The protein
interactions with metal ions are shown as cyan dotted lines.
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Figure 8.
Figure 8. Comparison of the AMP and 8-Br-AMP bound to
PDE4B. Schematic representation of the ligand-binding mode for
each molecule including the major hydrogen bond interactions
seen between each ligand and the active site.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
337,
355-365)
copyright 2004.
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