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PDBsum entry 20gs
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The ligandin (non-Substrate) binding site of human pi class glutathione transferase is located in the electrophile binding site (h-Site).
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Authors
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A.J.Oakley,
M.Lo bello,
M.Nuccetelli,
A.P.Mazzetti,
M.W.Parker.
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Ref.
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J Mol Biol, 1999,
291,
913-926.
[DOI no: ]
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PubMed id
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Abstract
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Glutathione S -transferases (GSTs) play a pivotal role in the detoxification of
foreign chemicals and toxic metabolites. They were originally termed ligandins
because of their ability to bind large molecules (molecular masses >400 Da),
possibly for storage and transport roles. The location of the ligandin site in
mammalian GSTs is still uncertain despite numerous studies in recent years. Here
we show by X-ray crystallography that the ligandin binding site in human pi
class GST P1-1 occupies part of one of the substrate binding sites. This work
has been extended to the determination of a number of enzyme complex crystal
structures which show that very large ligands are readily accommodated into this
substrate binding site and in all, but one case, causes no significant movement
of protein side-chains. Some of these molecules make use of a hitherto
undescribed binding site located in a surface pocket of the enzyme. This site is
conserved in most, but not all, classes of GSTs suggesting it may play an
important functional role.
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Figure 1.
Figure 1. Schematic representation of the inhibitors. (a)
Sulfasalazine. The numbering scheme is taken from [van der Sluis
and Spek 1990]. (b) S-Nonyl GSH; (c) Cibacron blue; (d)
bromosulfophthalein; (e) 2,4-dinitrophenyl GSH.
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Figure 3.
Figure 3. A comparison of the binding locations of GSH
conjugates derived from the various crystal structures of pi
class GSTs presented here. The superposition was based on
overlaying the coordinates of the respective N-terminal domains.
The ligands are overlayed on a schematic of the N-terminal
domain of the human pi class enzyme. (a) Stereo view showing all
inhibitors described in the text. The inhibitors are coloured as
follows: SLZ, yellow;S-nonyl GSH, cyan; CB, dark blue; BS no.1,
red; BS no. 2, magenta; DNP GSH, green. The side-chains of
Phe8 and Tyr108 are shown. (b) Comparison of the binding
locations of DNP GSH (denoted by yellow bonds) and BS no. 1
(denoted by red bonds). These pictures were generated with the
program MOLSCRIPT [Kraulis 1991].
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1999,
291,
913-926)
copyright 1999.
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Secondary reference #1
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Title
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The structures of human glutathione transferase p1-1 in complex with glutathione and various inhibitors at high resolution.
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Authors
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A.J.Oakley,
M.Lo bello,
A.Battistoni,
G.Ricci,
J.Rossjohn,
H.O.Villar,
M.W.Parker.
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Ref.
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J Mol Biol, 1997,
274,
84.
[DOI no: ]
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PubMed id
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Figure 3.
Figure 3. Schematic drawing of residues that interact with
the substrates and inhibitors. (a) GSH (C2 form, 100 K) and (b)
TER-117 (C2 form, 288 K). The key to the Figures is shown in
part (a). These Figures were produced using the program LIGPLOT
[Wallace et al 1995].
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Figure 7.
Figure 7. Superposition of the active sites of the
alpha-class hGST A1-1 [Sinning et al 1993], human mu-class GST
M2-2 [Raghunathan et al 1994] and human hGST P1-1 crystal
structures showing the fit of the inhibitor TER-117. The
structures are colored yellow, green and mauve, respectively.
The characteristic Mu-loop of the rat enzyme and the C-terminal
helix α9 of the alpha-class enzyme are shown. Residues likely
to collide with the phenyl ring of the inhibitor are
highlighted. This Figure was generated with the program package
INSIGHT II (Molecular Simulations Inc., San Diego, CA, USA.).
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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