Crystal structure of human glyoxalase I--evidence for gene duplication and 3D domain swapping.
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.
Cameron
A D
AD
Department of Molecular Biology, Uppsala University, Biomedical Center, Sweden.
Olin
B
B
Ridderström
M
M
Mannervik
B
B
Jones
T A
TA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007791:Lactoylglutathione Lyase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D007791:Lactoylglutathione Lyase; D005978:Glutathione; D015032:Zinc