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PDBsum entry 2feh
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Oxidoreductase
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PDB id
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2feh
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References listed in PDB file
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Key reference
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Title
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High-Resolution structure of human d-Glyceraldehyde-3-Phosphate dehydrogenase.
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Authors
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J.L.Jenkins,
J.J.Tanner.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2006,
62,
290-301.
[DOI no: ]
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PubMed id
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Abstract
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GAPDH (D-glyceraldehyde-3-phosphate dehydrogenase) is a multifunctional protein
that is a target for the design of antitrypanosomatid and anti-apoptosis drugs.
Here, the first high-resolution (1.75 Angstroms) structure of a human GAPDH is
reported. The structure shows that the intersubunit selectivity cleft that has
been leveraged in the design of antitrypanosomatid compounds is closed in human
GAPDH. Modeling of an anti-trypanosomatid GAPDH inhibitor in the human GAPDH
active site provides insights into the basis for the observed selectivity of
this class of inhibitor. Moreover, the high-resolution data reveal a new feature
of the cleft: water-mediated intersubunit hydrogen bonds that assist closure of
the cleft in the human enzyme. The structure is used in a computational
ligand-docking study of the small-molecule compound CGP-3466, which inhibits
apoptosis by preventing nuclear accumulation of GAPDH. Plausible binding sites
are identified in the adenosine pocket of the NAD(+)-binding site and in a
hydrophobic channel located in the center of the tetramer near the intersection
of the three molecular twofold axes. The structure is also used to build a
qualitative model of the complex between GAPDH and the E3 ubiquitin ligase
Siah1. The model suggests that the convex surface near GAPDH Lys227 interacts
with a large shallow groove of the Siah1 dimer. These results are discussed in
the context of the recently discovered NO-S-nitrosylation-GAPDH-Siah1 apoptosis
cascade.
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Figure 7.
Figure 7 Structures of HsGAPDH and Siah1 highlighting regions
that are important for GAPDH-Siah1 association. (a) HsGAPDH
tetramer viewed down the R axis. Subunits are colored as
follows: O, yellow; P, red; Q, green; R, blue. Residues that are
essential for complex formation with Siah1 are colored gray
(residues 222-240) and atoms of Lys227 are drawn as spheres. (b)
Homodimer of Siah1 from PDB entry 1k2f (Polekhina et al.,
2002[Polekhina, G., House, C. M., Traficante, N., Mackay, J. P.,
Relaix, F., Sassoon, D. A., Parker, M. W. & Bowtell, D. D.
(2002). Nature Struct. Biol. 9, 68-75.]). The two subunits of
Siah1 are colored cyan and violet. Residues that are essential
for interaction with GAPDH are colored yellow (residues 270-282).
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Figure 8.
Figure 8 Qualitative model of the HsGAPDH-Siah1 complex. (a)
Docked complex having the top score from PatchDock. A GAPDH
subunit is shown in green and the Siah1 dimer is shown in
cyan/violet. Only one subunit of the GAPDH dimer used for
docking is shown for clarity. GAPDH residues 222-240 are colored
gray. Siah1 residues 270-282 are colored yellow. GAPDH Lys227
and Siah1 Ser280 are drawn as spheres. (b) Model of a GAPDH
tetramer interacting with four Siah1 dimers. This model was
generated from the model in (a) using the symmetry of the GAPDH
tetramer. The view is looking down the GAPDH R axis. GAPDH
subunits are colored as follows: O, yellow; P, red; Q, green; R,
blue. Siah1 dimers are colored cyan/violet and salmon/slate. (c)
Surface representation of the model shown in (b).
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2006,
62,
290-301)
copyright 2006.
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