The Structure of Human 15-Lipoxygenase-2 with a Substrate Mimic [Lipids]

February 4th, 2014 by Kobe, M. J., Neau, D. B., Mitchell, C. E., Bartlett, S. G., Newcomer, M. E.

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, that projects from the amino terminal membrane-binding domain. The loop is flanked by two Ca2+-binding sites which confer Ca2+-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.