6NCF

The structure of Stable-5-Lipoxygenase bound to AKBA

Summary for 6NCF

• Entry DOI: 10.2210/pdb6ncf/pdb
• Descriptor: Arachidonate 5-lipoxygenase, FE (II) ION, (3alpha,8alpha,17alpha,18alpha)-3-(acetyloxy)-11-oxours-12-en-23-oic acid (3 entities in total)
• Functional Keywords: lipoxygenase, inhibitor, allostery, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 318481.07

Authors

Newcomer, M.E.,Gilbert, N.C.,Neau, D.B. (deposition date: 2018-12-11, release date: 2020-05-13, Last modification date: 2020-07-08)

Primary citation

Gilbert, N.C.,Gerstmeier, J.,Schexnaydre, E.E.,Borner, F.,Garscha, U.,Neau, D.B.,Werz, O.,Newcomer, M.E.
Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products.
Nat.Chem.Biol., 16:783-790, 2020

PubMed Abstract: Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.

PubMed: 32393899
DOI: 10.1038/s41589-020-0544-7

Experimental method

X-RAY DIFFRACTION (2.871 Å)