Crystal structure of 12-lipoxygenase catalytic-domain-inhibitor complex identifies a substrate-binding channel for catalysis.

Xu S, Mueser TC, Marnett LJ, Funk MO
Structure. 2012 20 (9): 1490-7

PMID: 22795085 · PMCID: PMC5226221 · DOI:10.1016/j.str.2012.06.003

Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 Å) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (16)

Animals Arachidonate 12-Lipoxygenase Biocatalysis Catalytic Domain Coordination Complexes Crystallography, X-Ray Hydrogen Bonding Hydrophobic and Hydrophilic Interactions Iron Lipoxygenase Inhibitors Models, Molecular Oxygen Phenylpropionates Protein Binding Protein Structure, Secondary Sus scrofa

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