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The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB

Nature Structural Biology volume 9, pages 348–352 (2002)Cite this article

Abstract

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 Å 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.

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Figure 1: Domain structure and reductase activity.
Figure 2: Conservation and structure of the MsrB domain.
Figure 3: Mirror-like relationship between the active sites of MsrB and MsrA domains.
Figure 4: Proposed reaction mechanism for MsrB catalysis.

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Acknowledgements

This research was supported by the National Institutes of Health and a grant from Hoffmann-La Roche. We are extremely grateful to the staff of the Advanced Light Source (ALS) Beamline 5.0.2 for assistance in data collection and M. Coca-Prados of the Yale University School of Medicine for the human CBS-1 cDNA clone.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Physics, Institute of Molecular Biology, 1229 University of Oregon, Eugene, 97403-1229, Oregon, USA

    W. Todd Lowther & Brian W. Matthews

  2. Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, 33431, Florida, USA

    Herbert Weissbach & Frantzy Etienne

  3. Department of Microbiology and Immunology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Nathan Brot

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  1. W. Todd Lowther
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Correspondence to Brian W. Matthews.

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Lowther, W., Weissbach, H., Etienne, F. et al. The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB. Nat Struct Mol Biol 9, 348–352 (2002). https://doi.org/10.1038/nsb783

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