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PDBsum entry 2fm0
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References listed in PDB file
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Key reference
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Title
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Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase.
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Authors
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Q.Huai,
Y.Sun,
H.Wang,
D.Macdonald,
R.Aspiotis,
H.Robinson,
Z.Huang,
H.Ke.
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Ref.
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J Med Chem, 2006,
49,
1867-1873.
[DOI no: ]
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PubMed id
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Abstract
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Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a
number of disorders including asthma and chronic obstructive pulmonary disease.
Here we report the biochemical characterization on the second generation
inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer (-)-1 (L-, IC50=43 nM) and
their cocrystal structures with PDE4D at 2.0 A resolution. Despite the 107-fold
affinity difference, both enantiomers interact with the same sets of residues in
the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to
preserve the pivotal interactions between the Mg-bound waters and the N-oxide of
pyridine. These structures support a model in which inhibitors are anchored by
the invariant glutamine at one end and the metal-pocket residues at another end.
This model provides explanations for most of the observed structure-activity
relationship and the metal ion dependency of the catechol-ether based inhibitors
and should facilitate their further design.
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