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Science 317 (5837): 510-512

Copyright © 2007 by the American Association for the Advancement of Science

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

Andrew D. Ferguson,1* Brian M. McKeever,1,5* Shihua Xu,1 Douglas Wisniewski,2 Douglas K. Miller,3,6 Ting-Ting Yamin,3 Robert H. Spencer,4,7 Lin Chu,1 Feroze Ujjainwalla,1 Barry R. Cunningham,2 Jilly F. Evans,3,8 Joseph W. Becker1{dagger}

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.

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.

{dagger} To whom correspondence should be addressed. E-mail: joseph_becker{at}merck.com


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