The structure of human 15-lipoxygenase-2 with a substrate mimic.
Publication Type:Journal Article
Source:J Biol Chem, Volume 289, Issue 12, p.8562-9 (2014)
Keywords:Arachidonate 15-Lipoxygenase, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Humans, Models, Molecular, Protein Binding, Protein Conformation
<p>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. </p>