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Published Online June 28, 2007
Science DOI: 10.1126/science.1144346

Reports

Submitted on April 27, 2007
Accepted on June 15, 2007

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

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

1 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
2 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA; Vitae Pharmaceuticals, Fort Washington, PA 19034, USA.
3 Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA.
4 Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA; Wyeth Research, Collegeville PA 19426, USA.
5 Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA.
6 Department of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA; Cara Therapeutics, Tarrytown NY 10591, USA.
7 Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA; Amira Pharmaceuticals, San Diego, CA 92121, USA.

* To whom correspondence should be addressed.
Joseph W. Becker , E-mail: joseph_becker{at}merck.com

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 Å resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, suggesting 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.


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