5X68

Crystal Structure of Human KMO

5X68 の概要

• エントリーDOI: 10.2210/pdb5x68/pdb
• 関連するPDBエントリー: 5X6P 5X6Q 5X6R
• 分子名称: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• 機能のキーワード: monooxygenase, flavin reduction, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion outer membrane ; Multi-pass membrane protein : O15229
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90141.34

構造登録者

Kim, H.T.,Hwang, K.Y. (登録日: 2017-02-21, 公開日: 2018-02-21, 最終更新日: 2025-04-09)

主引用文献

Kim, H.T.,Na, B.K.,Chung, J.,Kim, S.,Kwon, S.K.,Cha, H.,Son, J.,Cho, J.M.,Hwang, K.Y.
Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase
Cell Chem Biol, 25:426-438.e4, 2018

PubMed Abstract: Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via π-π interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal α helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors.

PubMed: 29429898
DOI: 10.1016/j.chembiol.2018.01.008

実験手法

X-RAY DIFFRACTION (2.1 Å)