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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2006-3-16
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pubmed:databankReference |
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pubmed:abstractText |
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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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-10712916,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-10741778,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-10828959,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-10846163,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-10889326,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-11470607,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-11513595,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12010850,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12166544,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12174704,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12270195,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12387865,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12444918,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12493749,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12773045,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12842049,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12920188,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-12955149,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-14609333,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-14668322,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-14727939,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15003452,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15147193,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15210993,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15260978,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15276712,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15514991,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15576036,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15639300,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15685167,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15763421,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15938621,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16539372-15994308
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1867-73
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:16539372-3',5'-Cyclic-AMP Phosphodiesterases,
pubmed-meshheading:16539372-Catalytic Domain,
pubmed-meshheading:16539372-Crystallography, X-Ray,
pubmed-meshheading:16539372-Cyclic N-Oxides,
pubmed-meshheading:16539372-Cyclic Nucleotide Phosphodiesterases, Type 4,
pubmed-meshheading:16539372-Enzyme Inhibitors,
pubmed-meshheading:16539372-Models, Molecular,
pubmed-meshheading:16539372-Molecular Structure,
pubmed-meshheading:16539372-Protein Binding,
pubmed-meshheading:16539372-Pyridines,
pubmed-meshheading:16539372-Stereoisomerism
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pubmed:year |
2006
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pubmed:articleTitle |
Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase.
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pubmed:affiliation |
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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