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Molecular basis of mitomycin C resistance in Streptomyces: Structure and function of the MRD protein

  1. Author:
    Martin, T. W.
    Dauter, Z.
    Devedjiev, Y.
    Sheffield, P.
    Jelen, F.
    He, M.
    Sherman, D. H.
    Otlewski, J.
    Derewenda, Z. S.
    Derewenda, U.

  2. Author Address

    Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA NCI, Frederick & Natl Brookhaven Lab, Upton, NY 11973 USA Univ Wroclaw, Inst Biochem & Mol Biol, PL-50137 Wroclaw, Poland Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA Univ Minnesota, Inst Biotechnol, Minneapolis, MN 55455 USA Derewenda U Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
    1. Year: 2002
  2. Journal: Structure
    1. 10
    2. 7
    3. Pages: 933-942
  4. Type of Article: Article
  1. Abstract:

    Mitomycin C (MC) is a potent anticancer agent. Streptomyces lavendulae, which produces MC, protects itself from the lethal effects of the drug by expressing several resistance proteins. One of them (MRD) binds MC and functions as a drug exporter. We report the crystal structure of MRD and its complex with an MC metabolite, 1,2-cis-1-hydroxy-2,7-diaminomitosene, at 1.5Angstrom resolution. The drug is sandwiched by pi-stacking interactions of His-38 and Trp-108. MRD is a dimer. The betaalphabetabetabeta fold of the MRD molecule is reminiscent of methylmalonyl-CoA epimerase, bleomycin resistance proteins, glyoxalase 1, and extradiol dioxygenases. The location of the binding site is identical to the ones in evolutionarily related enzymes, suggesting that the protein may have been recruited from a different metabolic pathway.

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