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 acid

Summary for 5NAB

• Entry DOI: 10.2210/pdb5nab/pdb
• Descriptor: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: kmo, oxidoreductase
• Biological source: Pseudomonas fluorescens
• Total number of polymer chains: 2
• Total formula weight: 104369.11

Authors

Rowland, P. (deposition date: 2017-02-27, release date: 2017-06-21, Last modification date: 2024-05-08)

Primary citation

Hutchinson, J.P.,Rowland, P.,Taylor, M.R.D.,Christodoulou, E.M.,Haslam, C.,Hobbs, C.I.,Holmes, D.S.,Homes, P.,Liddle, J.,Mole, D.J.,Uings, I.,Walker, A.L.,Webster, S.P.,Mowat, C.G.,Chung, C.W.
Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.
Nat Commun, 8:15827-15827, 2017

PubMed Abstract: 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.

PubMed: 28604669
DOI: 10.1038/ncomms15827

Experimental method

X-RAY DIFFRACTION (1.63 Å)