6N2W

The structure of Stable-5-Lipoxygenase bound to NDGA

6N2W の概要

• エントリーDOI: 10.2210/pdb6n2w/pdb
• 分子名称: Arachidonate 5-lipoxygenase, FE (II) ION, 4-[(2R,3S)-3-[(3,4-DIHYDROXYPHENYL)METHYL]-2-METHYLBUTYL]BENZENE-1,2-DIOL, ... (4 entities in total)
• 機能のキーワード: lipoxygenase, inhibitor, allostery, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 159286.54

構造登録者

Newcomer, M.E.,Gilbert, N.C.,Neau, D.B. (登録日: 2018-11-14, 公開日: 2020-05-13, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.71 Å)