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PDBsum entry 3map
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Oxidoreductase
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PDB id
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3map
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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 mechanisms of "off-On switch" of activities of human idh1 by tumor-Associated mutation r132h.
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Authors
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B.Yang,
C.Zhong,
Y.Peng,
Z.Lai,
J.Ding.
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Ref.
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Cell Res, 2010,
20,
1188-1200.
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PubMed id
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Abstract
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Human cytosolic NADP-IDH (IDH1) has recently been found to be involved in
tumorigenesis. Notably, the tumor-derived IDH1 mutations identified so far
mainly occur at Arg132, and mutation R132H is the most prevalent one. This
mutation impairs the oxidative IDH activity of the enzyme, but renders a new
reduction function of converting α-ketoglutarate (αKG) to 2-hydroxyglutarate.
Here, we report the structures of the R132H mutant IDH1 with and without
isocitrate (ICT) bound. The structural data together with mutagenesis and
biochemical data reveal a previously undefined initial ICT-binding state and
demonstrate that IDH activity requires a conformational change to a closed
pre-transition state. Arg132 plays multiple functional roles in the catalytic
reaction; in particular, the R132H mutation hinders the conformational changes
from the initial ICT-binding state to the pre-transition state, leading to the
impairment of the IDH activity. Our results describe for the first time that
there is an intermediate conformation that corresponds to an initial ICT-binding
state and that the R132H mutation can trap the enzyme in this conformation,
therefore shedding light on the molecular mechanism of the "off
switch" of the potentially tumor-suppressive IDH activity. Furthermore, we
proved the necessity of Tyr139 for the gained αKG reduction activity and
propose that Tyr139 may play a vital role by compensating the increased negative
charge on the C2 atom of αKG during the transfer of a hydride anion from NADPH
to αKG, which provides new insights into the mechanism of the "on
switch" of the hypothetically oncogenic reduction activity of IDH1 by this
mutation.
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