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PDBsum entry 2hgs
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Amine/carboxylate ligase
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PDB id
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2hgs
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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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Molecular basis of glutathione synthetase deficiency and a rare gene permutation event.
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Authors
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G.Polekhina,
P.G.Board,
R.R.Gali,
J.Rossjohn,
M.W.Parker.
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Ref.
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EMBO J, 1999,
18,
3204-3213.
[DOI no: ]
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PubMed id
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Abstract
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Glutathione synthetase (GS) catalyses the production of glutathione from
gamma-glutamylcysteine and glycine in an ATP-dependent manner. Malfunctioning of
GS results in disorders including metabolic acidosis, 5-oxoprolinuria,
neurological dysfunction, haemolytic anaemia and in some cases is probably
lethal. Here we report the crystal structure of human GS (hGS) at 2.1 A
resolution in complex with ADP, two magnesium ions, a sulfate ion and
glutathione. The structure indicates that hGS belongs to the recently identified
ATP-grasp superfamily, although it displays no detectable sequence identity with
other family members including its bacterial counterpart, Escherichia coli GS.
The difficulty in identifying hGS as a member of the family is due in part to a
rare gene permutation which has resulted in a circular shift of the conserved
secondary structure elements in hGS with respect to the other known ATP-grasp
proteins. Nevertheless, it appears likely that the enzyme shares the same
general catalytic mechanism as other ligases. The possibility of cyclic
permutations provides an insight into the evolution of this family and will
probably lead to the identification of new members. Mutations that lead to GS
deficiency have been mapped onto the structure, providing a molecular basis for
understanding their effects.
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Figure 3.
Figure 3 A ribbon representation of the dimer. The dimerization
unit of each monomer is shown in different colour and the lid
domains shown in mauve. The GS deficiency mutations are shown in
ball-and-stick. This figure was drawn with MOLSCRIPT (Kraulis,
1991).
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Figure 4.
Figure 4 Comparison of human and bacterial GS. (A)
Structure-based sequence alignment of hGS and ecGS. The
secondary structure and residue numbering of hGS are shown above
the alignment and the ecGS numbering below it. The secondary
structure of the conserved structural core elements of the
ATP-grasp superfamily are coloured as follows: the N-terminal
domain is red, the middle, lid domain is green, the C-terminal
domain is blue and the linker region (to the lid domain) in
orange. Additional secondary structures found in hGS are shown
in gray. Strictly conserved residues are highlighted in darkened
boxes and invariant residues of GS enzymes from eukaryotic
organisms are designated by asterisks. The complimentary
mutations and cis-peptide regions discussed in the text are
highlighted in the open boxes. The figure was produced using
ALSCRIPT (Barton, 1993). (B and C) Topological diagrams
highlighting the major structural elements of hGS and ecGS. The
colours refer to the structural cores conserved throughout the
ATP-grasp superfamily. (D and E) Ribbon diagrams of hGS and ecGS
using the same colour coding as in (A). The ribbon figures were
drawn with MOLSCRIPT (Kraulis, 1991).
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(1999,
18,
3204-3213)
copyright 1999.
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Secondary reference #1
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Title
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Sequencing and expression of a cdna for human glutathione synthetase.
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Authors
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R.R.Gali,
P.G.Board.
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Ref.
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Biochem J, 1995,
310,
353-358.
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PubMed id
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