Structure-based drug design on membrane protein targets: human integral membrane protein 5-lipoxygenase-activating protein.
Leukotrienes are biologically active lipid metabolites of arachidonic acid that are involved in inflammation and play a significant role in respiratory and cardiovascular disease. The integral nuclear membrane protein 5-lipoxygenase-activating protein (FLAP) is essential for leukotriene biosynthesis in response to cellular activation. The crystal structures of human FLAP with two inhibitors were recently determined. Inhibitors are bound within the lipid-exposed portion of FLAP, and the unexpected location of the inhibitor-binding site suggests a transport mechanism for arachidonic acid and provides functional insights into leukotriene biosynthesis. This chapter describes how this human integral membrane crystal structure was solved by pushing the limits of low-resolution structure determination and refinement, demonstrating how a low-resolution structure can impact biology and chemistry, and discusses future opportunities for structure-based drug design for this therapeutic target.
Discovery Sciences, AstraZeneca Pharmaceuticals, Waltham, MA, USA. adferg@gmail.com
Andrew D
AD
Ferguson
D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D058927:5-Lipoxygenase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins