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

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.

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