5nab

Pseudomonas fluorescens kynurenine 3-monooxygenase (KMO) in complex with 3-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acidPseudomonas fluorescens kynurenine 3-monooxygenase (KMO) in complex with 3-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid

Structural highlights 5nab is a 2 chain structure with sequence from Pseudomonas fluorescens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.63Å Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KMO_PSEFL Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Probably required for the synthesis of quinolinic acid and the siderophore quinolobactin. Publication Abstract from PubMed Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design. Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.,Hutchinson JP, Rowland P, Taylor MRD, Christodoulou EM, Haslam C, Hobbs CI, Holmes DS, Homes P, Liddle J, Mole DJ, Uings I, Walker AL, Webster SP, Mowat CG, Chung CW Nat Commun. 2017 Jun 12;8:15827. doi: 10.1038/ncomms15827. PMID:28604669 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Monooxygenase 3D structures

spinqualitylabelsall models 5nab, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image