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2fm0
From Proteopedia
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[[Image:2fm0.gif|left|200px]] | [[Image:2fm0.gif|left|200px]] | ||
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'''Crystal structure of PDE4D in complex with L-869298''' | '''Crystal structure of PDE4D in complex with L-869298''' | ||
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[[Category: Sun, Y.]] | [[Category: Sun, Y.]] | ||
[[Category: Wang, H.]] | [[Category: Wang, H.]] | ||
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| - | [[Category: | + | [[Category: Inhibitor selectivity]] |
| - | [[Category: | + | [[Category: Pde. enantiomer binding]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:03:10 2008'' | |
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Revision as of 01:03, 4 May 2008
Crystal structure of PDE4D in complex with L-869298
Overview
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.
About this Structure
2FM0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase., Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H, J Med Chem. 2006 Mar 23;49(6):1867-73. PMID:16539372 Page seeded by OCA on Sun May 4 04:03:10 2008
