title: Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.forename: Brian M
authors.initials: BM
authors.lastname: McKeever
authors.forename: Shihua
authors.initials: S
authors.lastname: Xu
authors.forename: Douglas
authors.initials: D
authors.lastname: Wisniewski
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Miller
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yamin
authors.forename: Robert H
authors.initials: RH
authors.lastname: Spencer
authors.forename: Lin
authors.initials: L
authors.lastname: Chu
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
authors.forename: Barry R
authors.initials: BR
authors.lastname: Cunningham
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Becker
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D009685:Nuclear Envelope / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007211:Indoles; D008565:Membrane Proteins; D021122:Protein Subunits; D011804:Quinolines; C078266:MK 0591; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase