5X6R

Crystal structure of Saccharomyces cerevisiae KMO in complex with Ro 61-8048

Summary for 5X6R

• Entry DOI: 10.2210/pdb5x6r/pdb
• Related: 5X68 5X6P 5X6Q
• Descriptor: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, 3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: monooxygenase, oxidoreductase
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• Cellular location: Mitochondrion outer membrane : P38169
• Total number of polymer chains: 2
• Total formula weight: 98241.16

Authors

Kim, H.T.,Hwang, K.Y. (deposition date: 2017-02-23, release date: 2018-02-21, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.911 Å)