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Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

DOI: 10.1038/ncomms15827 DOI Help

Authors: Jonathan P. Hutchinson (GlaxoSmithKline) , Paul Rowland (GlaxoSmithKline) , Mark R. D. Taylor (University of Edinburgh) , Erica M. Christodoulou (GlaxoSmithKline) , Carl Haslam (GlaxoSmithKline) , Clare I. Hobbs (GlaxoSmithKline) , Duncan S. Holmes (GlaxoSmithKline) , Paul Homes (GlaxoSmithKline) , John Liddle (GlaxoSmithKline) , Damian J. Mole (Medical Research Council Centre for Inflammation Research; University of Edinburgh) , Iain Uings (GlaxoSmithKline) , Ann L. Walker (GlaxoSmithKline) , Scott P. Webster (University of Edinburgh) , Christopher G. Mowat (University of Edinburgh) , Chun-Wa Chung (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 8

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 12279

Open Access Open Access

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.

Journal Keywords: Chemical biology; Drug discovery; X-ray crystallography

Diamond Keywords: Enzymes; Alzheimer's Disease; Huntington's Disease (HD)

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 21/06/2017 11:21

Documents:
ncomms15827.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)