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PDBsum entry 1fro
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Lactoylglutathione lyase
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PDB id
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1fro
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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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Crystal structure of human glyoxalase I--Evidence for gene duplication and 3d domain swapping.
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Authors
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A.D.Cameron,
B.Olin,
M.Ridderström,
B.Mannervik,
T.A.Jones.
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Ref.
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Embo J, 1997,
16,
3386-3395.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
86%.
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Abstract
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The zinc metalloenzyme glyoxalase I catalyses the glutathione-dependent
inactivation of toxic methylglyoxal. The structure of the dimeric human enzyme
in complex with S-benzyl-glutathione has been determined by multiple isomorphous
replacement (MIR) and refined at 2.2 A resolution. Each monomer consists of two
domains. Despite only low sequence homology between them, these domains are
structurally equivalent and appear to have arisen by a gene duplication. On the
other hand, there is no structural homology to the 'glutathione binding domain'
found in other glutathione-linked proteins. 3D domain swapping of the N- and
C-terminal domains has resulted in the active site being situated in the dimer
interface, with the inhibitor and essential zinc ion interacting with side
chains from both subunits. Two structurally equivalent residues from each domain
contribute to a square pyramidal coordination of the zinc ion, rarely seen in
zinc enzymes. Comparison of glyoxalase I with other known structures shows the
enzyme to belong to a new structural family which includes the Fe2+-dependent
dihydroxybiphenyl dioxygenase and the bleomycin resistance protein. This
structural family appears to allow members to form with or without domain
swapping.
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Figure 1.
Figure 1 Schematic representation of glyoxalase I. (A) Monomer;
(B) dimer. The dimer has been colour ramped according to residue
number, starting with red at the N-terminus of one molecule,
passing through yellow at the C-terminus of that molecule and
finishing with blue at the C-terminus of the other monomer. The
zinc and its coordinating residues are shown in a ball and stick
representation with the zinc coloured green. The active site is
situated in a barrel which is formed only on dimerization.
Residue 114 is situated at the end of the red/yellow domain and
residue 123 at the beginning of the blue/green domain (see the
text). Prepared using MOLSCRIPT (Kraulis, 1991) modified by
R.Esnouf (Oxford University, unpublished). (C) A similar view of
the dihydroxybiphenyl dioxygenase (DHBD) enzyme (Han et al.,
1995) after superposition on the human glyoxalase I enzyme.
Again the molecule has been colour ramped according to residue
number, starting with red at the N-terminus and finishing with
blue at the C-terminus. Despite having only 14% sequence
identity (using the structures to align the sequences), 79 C
 pairs
from the C-terminal domains of this enzyme (blue and green) can
be aligned on glyoxalase I with an r.m.s.d. of 2 Å. The
colouring scheme clearly shows that the suggested domain
swapping in glyoxalase I is not present in DHBD. The ferrous
iron seen in DHBD is situated in a similar position to one of
the zincs in glyoxalase I. The residues coordinating the iron
are structurally equivalent to those binding the zinc.
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Figure 5.
Figure 5 Proposed reaction mechanism for glyoxalase I. A
shielded base (B) is proposed to abstract the proton from the C1
atom of the hemithioacetal of glutathione and a 2-oxoaldehyde
and then reprotonate at C2.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Embo J
(1997,
16,
3386-3395)
copyright 1997.
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