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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
Mutation of a Critical Arginine in Microsomal Prostaglandin E Synthase-1 Shifts the Isomerase Activity to a Reductase Activity That Converts Prostaglandin H2 into Prostaglandin F2{alpha}.
T. Hammarberg, M. Hamberg, A. Wetterholm, H. Hansson, B. Samuelsson, and J. Z. Haeggstrom (2009)
J. Biol. Chem.
284, 301-305
|Abstract »|Full Text »|PDF »
The nuclear membrane organization of leukotriene synthesis.
A. K. Mandal, P. B. Jones, A. M. Bair, P. Christmas, D. Miller, T.-t. D. Yamin, D. Wisniewski, J. Menke, J. F. Evans, B. T. Hyman, et al. (2008)
PNAS
105, 20434-20439
|Abstract »|Full Text »|PDF »
Leukotriene modifiers in the treatment of cardiovascular diseases.
G. Riccioni, V. Capra, N. D'Orazio, T. Bucciarelli, and L. A. Bazzano (2008)
J. Leukoc. Biol.
84, 1374-1378
|Abstract »|Full Text »|PDF »
Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors.
A. Maekawa, Y. Kanaoka, W. Xing, and K. F. Austen (2008)
PNAS
105, 16695-16700
|Abstract »|Full Text »|PDF »
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.
To whom correspondence should be addressed. E-mail: 
