5FN0

Crystal structure of Pseudomonas fluorescens kynurenine-3- monooxygenase (KMO) in complex with GSK180

5FN0 の概要

• エントリーDOI: 10.2210/pdb5fn0/pdb
• 分子名称: KYNURENINE 3-MONOOXYGENASE, FLAVIN-ADENINE DINUCLEOTIDE, 3-(5,6-DICHLORO-2-OXOBENZO[D]OXAZOL-3(2H)-YL)PROPANOIC ACID, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, kmo
• 由来する生物種: PSEUDOMONAS FLUORESCENS
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 207204.57

構造登録者

Mole, D.J.,Webster, S.P.,Uings, I.,Zheng, X.,Binnie, M.,Wilson, K.,Hutchinson, J.P.,Mirguet, O.,Walker, A.,Beaufils, B.,Ancellin, N.,Trottet, L.,Beneton, V.,Mowat, C.G.,Wilkinson, M.,Rowland, P.,Haslam, C.,McBride, A.,Homer, N.Z.M.,Baily, J.E.,Sharp, M.G.F.,Garden, O.J.,Hughes, J.,Howie, S.E.M.,Holmes, D.,Liddle, J.,Iredale, J.P. (登録日: 2015-11-10, 公開日: 2016-01-13, 最終更新日: 2024-05-08)

主引用文献

Mole, D.J.,Webster, S.P.,Uings, I.,Zheng, X.,Binnie, M.,Wilson, K.,Hutchinson, J.P.,Mirguet, O.,Walker, A.,Beaufils, B.,Ancellin, N.,Trottet, L.,Beneton, V.,Mowat, C.G.,Wilkinson, M.,Rowland, P.,Haslam, C.,Mcbride, A.,Homer, N.Z.,Baily, J.E.,Sharp, M.G.,Garden, O.J.,Hughes, J.,Howie, S.E.,Holmes, D.S.,Liddle, J.,Iredale, J.P.
Kynurenine-3-Monooxygenase Inhibition Prevents Multiple Organ Failure in Rodent Models of Acute Pancreatitis.
Nat.Med. (N.Y.), 22:202-, 2016

PubMed Abstract: Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

PubMed: 26752518
DOI: 10.1038/NM.4020

実験手法

X-RAY DIFFRACTION (3.19 Å)