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Structure and function of L -threonine-3-dehydrogenase from the parasitic protozoan Trypanosoma brucei revealed by X-ray crystallography and geometric simulations
DOI:
10.1107/S2059798318009208
Authors:
Eyram
Adjogatse
(University College London)
,
Peter
Erskine
(University College London)
,
Stephen A.
Wells
(University of Bath)
,
John M.
Kelly
(London School of Hygiene and Tropical Medicine)
,
Jonathan D.
Wilden
(University College London)
,
A. W. Edith
Chan
(University College London)
,
David
Selwood
(University College London)
,
Alun
Coker
(University College London)
,
Steve
Wood
(University College London)
,
Jonathan B.
Cooper
(University College London)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Acta Crystallographica Section D Structural Biology
, VOL 74
, PAGES 861 - 876
State:
Published (Approved)
Published:
September 2018
Diamond Proposal Number(s):
1372
Abstract: Two of the world's most neglected tropical diseases, human African trypanosomiasis (HAT) and Chagas disease, are caused by protozoan parasites of the genus Trypanosoma. These organisms possess specialized metabolic pathways, frequently distinct from those in humans, which have potential to be exploited as novel drug targets. This study elucidates the structure and function of L-threonine-3-dehydrogenase (TDH) from T. brucei, the causative pathogen of HAT. TDH is a key enzyme in the metabolism of L-threonine, and an inhibitor of TDH has been shown to have trypanocidal activity in the procyclic form of T. brucei. TDH is a nonfunctional pseudogene in humans, suggesting that it may be possible to rationally design safe and specific therapies for trypanosomiasis by targeting this parasite enzyme. As an initial step, the TDH gene from T. brucei was expressed and the three-dimensional structure of the enzyme was solved by X-ray crystallography. In multiple crystallographic structures, T. brucei TDH is revealed to be a dimeric short-chain dehydrogenase that displays a considerable degree of conformational variation in its ligand-binding regions. Geometric simulations of the structure have provided insight into the dynamic behaviour of this enzyme. Furthermore, structures of TDH bound to its natural substrates and known inhibitors have been determined, giving an indication of the mechanism of catalysis of the enzyme. Collectively, these results provide vital details for future drug design to target TDH or related enzymes.
Journal Keywords: protein crystallography; structural biology; threonine metabolism; trypanosomiasis; geometric simulations
Diamond Keywords: Sleeping Sickness; Enzymes
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I02-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)
Other Facilities: ESRF
Added On:
13/09/2018 09:08
Discipline Tags:
Infectious Diseases
Disease in the Developing World
Health & Wellbeing
Structural biology
Drug Discovery
Life Sciences & Biotech
Parasitology
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)