Crystal Structure of Inhibitor-Bound Human 5-Lipoxygenase—Activating Protein.

LIPOXYGENASES; MEMBRANE proteins; LEUKOTRIENES; X-ray crystallography; BIOSYNTHESIS; ARACHIDONIC acid; CARDIOVASCULAR diseases; OXIDATION; ORGANIC synthesis

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. [ABSTRACT FROM AUTHOR]

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