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Targeted molecular dynamics simulation studies of binding and conformational changes in E. coli MurD

Authors

  • Andrej Perdih,

    1. Laboratory for Molecular Modelling and NMR Spectroscopy, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
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  • Miha Kotnik,

    1. Lek Pharmaceuticals d.d., Drug Discovery, Verovs̆kova 57, 1526 Ljubljana, Slovenia
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  • Milan Hodoscek,

    1. Laboratory for Molecular Modelling and NMR Spectroscopy, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
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  • Tom Solmajer

    Corresponding author
    1. Laboratory for Molecular Modelling and NMR Spectroscopy, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
    2. Lek Pharmaceuticals d.d., Drug Discovery, Verovs̆kova 57, 1526 Ljubljana, Slovenia
    • National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
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Abstract

Enzymes involved in the biosynthesis of bacterial peptidoglycan, an essential cell wall polymer unique to prokaryotic cells, represent a highly interesting target for antibacterial drug design. Structural studies of E. coli MurD, a three-domain ATP hydrolysis driven muramyl ligase revealed two inactive open conformations of the enzyme with a distinct C-terminal domain position. It was hypothesized that the rigid body rotation of this domain brings the enzyme to its closed active conformation, a structure, which was also determined experimentally. Targeted molecular dynamics 1 ns-length simulations were performed in order to examine the substrate binding process and gain insight into structural changes in the enzyme that occur during the conformational transitions into the active conformation. The key interactions essential for the conformational transitions and substrate binding were identified. The results of such studies provide an important step toward more powerful exploitation of experimental protein structures in structure-based inhibitor design. Proteins 2007. © 2007 Wiley-Liss, Inc.

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