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Crystal Structure of Inhibitor-Bound Human 5-Lipoxygenase-Activating Protein
Andrew D. Ferguson,1*Brian M. McKeever,1,5*Shihua Xu,1Douglas Wisniewski,2Douglas K. Miller,3,6Ting-Ting Yamin,3Robert H. Spencer,4,7Lin Chu,1Feroze Ujjainwalla,1Barry R. Cunningham,2Jilly F. Evans,3,8Joseph W. Becker1
Leukotrienes are proinflammatory products of arachidonic acidoxidation by 5-lipoxygenase that have been shown to be involvedin respiratory and cardiovascular diseases. The integral membraneprotein FLAP is essential for leukotriene biosynthesis. We describethe x-ray crystal structures of human FLAP in complex with twoleukotriene biosynthesis inhibitors at 4.0 and 4.2 angstromresolution, respectively. The structures show that inhibitorsbind in membrane-embedded pockets of FLAP, which suggests howthese inhibitors prevent arachidonic acid from binding to FLAPand subsequently being transferred to 5-lipoxygenase, therebypreventing leukotriene biosynthesis. This structural informationprovides a platform for the development of therapeutics forrespiratory and cardiovascular diseases.
1 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. 2 Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. 3 Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. 4 Department of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA. 5 Vitae Pharmaceuticals, Fort Washington, PA 19034, USA. 6 Wyeth Research, Collegeville, PA 19426, USA. 7 Cara Therapeutics, Tarrytown, NY 10591, USA. 8 Amira Pharmaceuticals, San Diego, CA 92121, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: joseph_becker{at}merck.com
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