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PDBsum entry 3wxl
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References listed in PDB file
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Key reference
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Title
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Molecular basis for the reverse reaction of african human trypanosomes glycerol kinase.
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Authors
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E.O.Balogun,
D.K.Inaoka,
T.Shiba,
Y.Kido,
C.Tsuge,
T.Nara,
T.Aoki,
T.Honma,
A.Tanaka,
M.Inoue,
S.Matsuoka,
P.A.Michels,
K.Kita,
S.Harada.
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Ref.
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Mol Microbiol, 2014,
94,
1315-1329.
[DOI no: ]
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PubMed id
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Abstract
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The glycerol kinase (GK) of African human trypanosomes is compartmentalized in
their glycosomes. Unlike the host GK, which under physiological conditions
catalyzes only the forward reaction (ATP-dependent glycerol phosphorylation),
trypanosome GK can additionally catalyze the reverse reaction. In fact, owing to
this unique reverse catalysis, GK is potentially essential for the parasites
survival in the human host, hence a promising drug target. The mechanism of its
reverse catalysis was unknown; therefore, it was not clear if this ability was
purely due to its localization in the organelles or whether structure-based
catalytic differences also contribute. To investigate this lack of information,
the X-ray crystal structure of this protein was determined up to 1.90 Å
resolution, in its unligated form and in complex with three natural ligands.
These data, in conjunction with results from structure-guided mutagenesis
suggests that the trypanosome GK is possibly a transiently autophosphorylating
threonine kinase, with the catalytic site formed by non-conserved residues. Our
results provide a series of structural peculiarities of this enzyme, and gives
unexpected insight into the reverse catalysis mechanism. Together, they provide
an encouraging molecular framework for the development of trypanosome
GK-specific inhibitors, which may lead to the design of new and safer
trypanocidal drug(s).
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