Publication Date:
2007-06-30
Description:
Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ferguson, Andrew D -- McKeever, Brian M -- Xu, Shihua -- Wisniewski, Douglas -- Miller, Douglas K -- Yamin, Ting-Ting -- Spencer, Robert H -- Chu, Lin -- Ujjainwalla, Feroze -- Cunningham, Barry R -- Evans, Jilly F -- Becker, Joseph W -- New York, N.Y. -- Science. 2007 Jul 27;317(5837):510-2. Epub 2007 Jun 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17600184" target="_blank"〉PubMed〈/a〉
Keywords:
5-Lipoxygenase-Activating Proteins
;
Arachidonate 5-Lipoxygenase/metabolism
;
Arachidonic Acid/metabolism
;
Binding Sites
;
Carrier Proteins/antagonists & inhibitors/*chemistry/genetics/metabolism
;
Catalytic Domain
;
Crystallography, X-Ray
;
Cytosol/chemistry
;
Humans
;
Hydrophobic and Hydrophilic Interactions
;
Indoles/*chemistry/metabolism/pharmacology
;
Membrane Proteins/antagonists & inhibitors/*chemistry/genetics/metabolism
;
Models, Molecular
;
Mutagenesis
;
Nuclear Envelope/chemistry
;
Protein Conformation
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Protein Subunits/chemistry
;
Quinolines/*chemistry/metabolism/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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