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J Biol Chem. 2014 Mar 21;289(12):8562-9. doi: 10.1074/jbc.M113.543777. Epub 2014 Feb 4.

The structure of human 15-lipoxygenase-2 with a substrate mimic.

Author information

1
From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 and.

Abstract

Atherosclerosis is associated with chronic inflammation occurring over decades. The enzyme 15-lipoxygenase-2 (15-LOX-2) is highly expressed in large atherosclerotic plaques, and its activity has been linked to the progression of macrophages to the lipid-laden foam cells present in atherosclerotic plaques. We report here the crystal structure of human 15-LOX-2 in complex with an inhibitor that appears to bind as a substrate mimic. 15-LOX-2 contains a long loop, composed of hydrophobic amino acids, which projects from the amino-terminal membrane-binding domain. The loop is flanked by two Ca(2+)-binding sites that confer Ca(2+)-dependent membrane binding. A comparison of the human 15-LOX-2 and 5-LOX structures reveals similarities at the active sites, as well striking differences that can be exploited for design of isoform-selective inhibitors.

KEYWORDS:

Atherosclerosis; Eicosanoid-specific Enzymes; Fatty Acid Oxidation; Lipoxygenase Pathway; Protein Structure

PMID:
24497644
PMCID:
PMC3961679
DOI:
10.1074/jbc.M113.543777
[Indexed for MEDLINE]
Free PMC Article

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