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

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.

SUBMITTER: Kobe MJ

PROVIDER: S-EPMC3961679 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Kobe Matthew J MJ Neau David B DB Mitchell Caitlin E CE Bartlett Sue G SG Newcomer Marcia E ME

The Journal of biological chemistry 20140204 12

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 ...[more]

PMID: 24497644

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Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663.

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2010-12-16 | GSE15827 | GEO

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