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Solution structures of Mycobacterium tuberculosis thioredoxin C and models of intact thioredoxin system suggest new approaches to inhibitor and drug design

Authors

  • Andrew L. Olson,

    1. Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201
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    • Andrew L. Olson's current address is Department of Structural and Molecular Biology, North Carolina State University, Raleigh, North Carolina, 27695.

  • Terrence S. Neumann,

    1. Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201
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  • Sheng Cai,

    1. Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201
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    • Terrence S. Neumann's current address is Department of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI 53097.

  • Daniel S. Sem

    Corresponding author
    1. Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201
    • Department of Pharmaceutical Sciences, Concordia University Wisconsin, 12800 N. Lake Shore Dr., Mequon, WI 53097
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Abstract

Here, we report the NMR solution structures of Mycobacterium tuberculosis (M. tuberculosis) thioredoxin C in both oxidized and reduced states, with discussion of structural changes that occur in going between redox states. The NMR solution structure of the oxidized TrxC corresponds closely to that of the crystal structure, except in the C-terminal region. It appears that crystal packing effects have caused an artifactual shift in the α4 helix in the previously reported crystal structure, compared with the solution structure. On the basis of these TrxC structures, chemical shift mapping, a previously reported crystal structure of the M. tuberculosis thioredoxin reductase (not bound to a Trx) and structures for intermediates in the E. coli thioredoxin catalytic cycle, we have modeled the complete M. tuberculosis thioredoxin system for the various steps in the catalytic cycle. These structures and models reveal pockets at the TrxR/TrxC interface in various steps in the catalytic cycle, which can be targeted in the design of uncompetitive inhibitors as potential anti-mycobacterial agents, or as chemical genetic probes of function. © Proteins 2013. © 2012 Wiley Periodicals, Inc.

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