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.
From the Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803 and.
Matthew J
MJ
Kobe
David B
DB
Neau
Caitlin E
CE
Mitchell
Sue G
SG
Bartlett
Marcia E
ME
Newcomer
D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase
Atherosclerosis; Eicosanoid-specific Enzymes; Fatty Acid Oxidation; Lipoxygenase Pathway; Protein Structure