The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB.
Methionine sulfoxide reductases (Msr) protect against oxidative damage that can contribute to cell death. The tandem Msr domains (MsrA and MsrB) of the pilB protein from Neisseria gonorrhoeae each reduce different epimeric forms of methionine sulfoxide. The overall fold of the MsrB domain revealed by the 1.85 A crystal structure shows no resemblance to the previously determined MsrA structures from other organisms. Despite the lack of homology, the active sites show approximate mirror symmetry. In each case, conserved amino acid motifs mediate the stereo-specific recognition and reduction of the substrate. Unlike the MsrA domain, the MsrB domain activates the cysteine or selenocysteine nucleophile through a unique Cys-Arg-Asp/Glu catalytic triad. The collapse of the reaction intermediate most likely results in the formation of a sulfenic or selenenic acid moiety. Regeneration of the active site occurs through a series of thiol-disulfide exchange steps involving another active site Cys residue and thioredoxin. These observations have broad implications for modular catalysis, antibiotic drug design and continuing longevity studies in mammals.
Lowther
W Todd
WT
Institute of Molecular Biology, Howard Hughes Medical Institute and Department of Physics, 1229 University of Oregon, Eugene, Oregon 97403-1229, USA.
Weissbach
Herbert
H
Etienne
Frantzy
F
Brot
Nathan
N
Matthews
Brian W
BW
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051150:Methionine Sulfoxide Reductases; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009344:Neisseria gonorrhoeae / Q000201:enzymology*; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D010088:Oxidoreductases; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; C068255:pilB protein, Bacteria