2fm0: Difference between revisions

Revision as of 04:03, 4 May 2008

Crystal structure of PDE4D in complex with L-869298

OverviewOverview

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 StructureAbout this Structure

2FM0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

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

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OCA

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 [[Image:2fm0.gif|left|200px]]
- {{Structure
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-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span>
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-|GENE= PDE4D2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_2fm0|  PDB=2fm0  |  SCENE=  }}
-|RELATEDENTRY=[[2fm5|2FM5]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fm0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fm0 OCA], [http://www.ebi.ac.uk/pdbsum/2fm0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2fm0 RCSB]</span>
-}}
 '''Crystal structure of PDE4D in complex with L-869298'''
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 [[Category: Sun, Y.]]
 [[Category: Wang, H.]]
-[[Category: camp signalling]]
+[[Category: Camp signalling]]
-[[Category: crystal structure]]
+[[Category: Crystal structure]]
-[[Category: inhibitor selectivity]]
+[[Category: Inhibitor selectivity]]
-[[Category: pde. enantiomer binding]]
+[[Category: Pde. enantiomer binding]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 04:03:10 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:04:35 2008''