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PDBsum entry 5k4t
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Oxidoreductase
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PDB id
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5k4t
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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E.Adjogatse,
P.Erskine,
S.A.Wells,
J.M.Kelly,
J.D.Wilden,
A.W.E.Chan,
D.Selwood,
A.Coker,
S.Wood,
J.B.Cooper.
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Ref.
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Acta Crystallogr D Struct Biol, 2018,
74,
861-876.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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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.
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