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PDBsum entry 2vr7
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Oxidoreductase
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PDB id
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2vr7
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References listed in PDB file
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Key reference
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Title
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Structures of the g85r variant of sod1 in familial amyotrophic lateral sclerosis.
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Authors
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X.Cao,
S.V.Antonyuk,
S.V.Seetharaman,
L.J.Whitson,
A.B.Taylor,
S.P.Holloway,
R.W.Strange,
P.A.Doucette,
J.S.Valentine,
A.Tiwari,
L.J.Hayward,
S.Padua,
J.A.Cohlberg,
S.S.Hasnain,
P.J.Hart.
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Ref.
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J Biol Chem, 2008,
283,
16169-16177.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1)
cause a dominant form of the progressive neurodegenerative disease amyotrophic
lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant
develop paralytic symptoms concomitant with the appearance of SOD1-enriched
proteinaceous inclusions in their neural tissues. The process(es) through which
misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not
understood. Here we present structures of the human G85R SOD1 variant determined
by single crystal x-ray diffraction. Alterations in structure of the
metal-binding loop elements relative to the wild type enzyme suggest a molecular
basis for the metal ion deficiency of the G85R SOD1 protein observed in the
central nervous system of transgenic mice and in purified recombinant G85R SOD1.
These findings support the notion that metal-deficient and/or disulfide-reduced
mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral
sclerosis.
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Figure 2.
FIGURE 2. The G85R mutation site and the copper- and
zinc-binding sites. The wild type protein is shown in yellow. A,
three of the four conformations observed in the 10 unique
subunits of the four crystal structures are shown in light blue,
green, and pink, respectively (see text). Copper and zinc ions
are represented as cyan and gray spheres, respectively. The dual
hydrogen bonds formed by Asp^124 to the copper ligand His^46 and
the zinc ligand His^71 as well as the hydrogen bonding network
between Pro^74, Arg^79, and Asp^101 are shown as dotted lines.
B, the image is the same as in A except rotated  90°
around the horizontal and vertical axes in the plane of the
page. The electrostatic loop has been removed for clarity. C,
the location of the three proline residues of the zinc loop (see
text). The disulfide loop (residues 50-62), a substructure of
the zinc loop, is shown in green. The remainder of the zinc loop
containing the zinc-binding ligands, residues 63-83, is shown in
blue. Pro^62, Pro^66, and Pro^74 in the zinc-bound conformation
of the zinc loop are shown in magenta. The altered position of
the five-membered ring of Pro^74 and the Arg^85 side chain are
shown in orange. The hydrogen bond normally found between the
carbonyl oxygen of Pro^74 and the guanidinium group of Arg^79 is
disrupted. D, structural state four (see text) found in G85R
subunits C, E, and F (see Table 2). The absence of electron
density around the  carbon and the Arg^85
side chain indicates that this residue is conformationally
mobile, sampling many positions. This movement is correlated
with both zinc deficiency in the zinc site and disorder of the
zinc and electrostatic loop elements.
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Figure 4.
FIGURE 4. A novel water molecule gains access to the active
site area in the three subunits with a displaced 85-86 peptide
bond (see also Table 2 and the text). The wild type enzyme is
shown in yellow, and the G85R SOD1 mutant is shown in pink. The
water molecule gaining access to zinc site in the G85R structure
is shown as a green sphere.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
16169-16177)
copyright 2008.
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