Kinetoplastid parasites cause a number of neglected tropical diseases that present a pressing crisis to the public health of developing countries.<i> Leishmania major</i> pteridine reductase (PTR1) provides an alternate pathway for folate reduction, which ultimately confers methotrexate resistance to parasites and complicates the design of selective substrate-like inhibitors. PTR1 has a homotetrameric structure and most existing inhibitors target the substrate-binding site. Although PTR1 is treated as a functional tetramer, there is no cooperativity between subunits and it has yet to be definitively established if catalytic activity requires tetrameric structure. Our previous work has shown that this tetrameric interface contains multiple computationally predicted hot-spots, clustered in a few short interface loops. This presentation explores the catalytic activity and multimeric state of PTR1 interface mutants with activity assays, chemical cross-linking, and interface-derived peptides.

Probing the tetrameric structure of <i>Leishmania major </i>pteridine reductase (PTR1) with point mutations and interface-derived peptides

255th National Meeting (2018)

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Probing the tetrameric structure of Leishmania major pteridine reductase (PTR1) with point mutations and interface-derived peptides