Abstract
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.
MeSH terms
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5-Lipoxygenase-Activating Proteins
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Arachidonate 5-Lipoxygenase / metabolism
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Arachidonic Acid / metabolism
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Binding Sites
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / chemistry*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Catalytic Domain
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Crystallography, X-Ray
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Cytosol / chemistry
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Humans
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Hydrophobic and Hydrophilic Interactions
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacology
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / chemistry*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Models, Molecular
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Mutagenesis
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Nuclear Envelope / chemistry
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Protein Conformation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Protein Subunits / chemistry
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Quinolines / chemistry*
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Quinolines / metabolism
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Quinolines / pharmacology
Substances
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5-Lipoxygenase-Activating Proteins
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ALOX5AP protein, human
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Carrier Proteins
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Indoles
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Membrane Proteins
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Protein Subunits
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Quinolines
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MK 0591
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Arachidonic Acid
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Arachidonate 5-Lipoxygenase