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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 DOI Help

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)