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NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosphoenolpyruvate:sugar phosphotransferase enzyme I

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Abstract

Starting from the NMR structure of the binary complex between the N-terminal domain of the unphosphorylated enzyme I (EIN) of the phosphoenolpyruvate:sugar phosphotransferase (PTS) and the histidine-containing phosphocarrier protein (HPr), a molecular model of the phosphorylated transition state of the related complex was established using constrained simulated annealing. The coordinates of the phosphorylated EIN enzyme were then used in a second step for flexible docking of a decapeptide inhibitor of EIN whose enzyme-bound conformation itself was determined by NMR using transferred nuclear Overhauser effects. Two phosphorylation models of the peptide inhibitor were investigated and shown to be both functional. Interestingly, one model is very similar to that of the complex between EIN and its natural substrate HPr. The present study demonstrates that NMR-guided flexible docking constitutes an interesting tool for docking highly flexible peptide ligands and facilitates the upcoming protein-based design of nonpeptide EIN inhibitors for discovering new antibiotics.

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Authors and Affiliations

  1. Department of Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland

    Didier Rognan, Gerd Folkers & Oliver Zerbe

  2. ARPIDA AG, Münchenstein, Switzerland

    Seema Mukhija

Authors
  1. Didier Rognan
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  2. Seema Mukhija
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  3. Gerd Folkers
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  4. Oliver Zerbe
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Rognan, D., Mukhija, S., Folkers, G. et al. NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosphoenolpyruvate:sugar phosphotransferase enzyme I. J Comput Aided Mol Des 15, 103–115 (2001). https://doi.org/10.1023/A:1008145813315

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