Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein.

Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.

Science (New York, N.Y.) 2007 Jul 27

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Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-li poxygenase 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.

Citation

Andrew D Ferguson, Brian M McKeever, Shihua Xu, Douglas Wisniewski, Douglas K Miller, Ting-Ting Yamin, Robert H Spencer, Lin Chu, Feroze Ujjainwalla, Barry R Cunningham, Jilly F Evans, Joseph W Becker. Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science (New York, N.Y.). 2007 Jul 27;317(5837):510-2