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Structure-Based Drug Design on Membrane Protein Targets: Human Integral Membrane Protein 5-Lipoxygenase-Activating Protein

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Book cover Structure-Based Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 841))

Abstract

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.

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  1. Discovery Sciences, AstraZeneca Pharmaceuticals, Waltham, MA, USA

    Andrew D. Ferguson

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  1. Andrew D. Ferguson
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Correspondence to Andrew D. Ferguson .

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  1. Trius Therapeutics, Nancy Ridge Dr. 6310, San Diego, 92121, California, USA

    Leslie W. Tari

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Ferguson, A.D. (2012). Structure-Based Drug Design on Membrane Protein Targets: Human Integral Membrane Protein 5-Lipoxygenase-Activating Protein. In: Tari, L. (eds) Structure-Based Drug Discovery. Methods in Molecular Biology, vol 841. Humana Press. https://doi.org/10.1007/978-1-61779-520-6_12

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  • DOI: https://doi.org/10.1007/978-1-61779-520-6_12

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