Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
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
The editors suggest the following Related Resources on Science sites:
In Science Signaling
EDITORS' CHOICE
Valda J. Vinson (31 July 2007) Sci. STKE2007 (397), tw275.
[DOI: 10.1126/stke.3972007tw275] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Structural basis for induced formation of the inflammatory mediator prostaglandin E2.
C. Jegerschold, S.-C. Pawelzik, P. Purhonen, P. Bhakat, K. R. Gheorghe, N. Gyobu, K. Mitsuoka, R. Morgenstern, P.-J. Jakobsson, and H. Hebert (2008)
PNAS
105, 11110-11115
|Abstract »|Full Text »|PDF »
Transmembrane segment enhanced labeling as a tool for the backbone assignment of {alpha}-helical membrane proteins.
S. Reckel, S. Sobhanifar, B. Schneider, F. Junge, D. Schwarz, F. Durst, F. Lohr, P. Guntert, F. Bernhard, and V. Dotsch (2008)
PNAS
105, 8262-8267
|Abstract »|Full Text »|PDF »
Vertebrate Membrane Proteins: Structure, Function, and Insights from Biophysical Approaches.