Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Leah S. Torrie, David A. Robinson, Michael G. Thomas, Judith V. Hobrath, Sharon M. Shepherd, John M. Post, Eun Jung Ko, Rafael Alves Ferreira, Claire J. Mackenzie, Karolina Wrobel, Darren P. Edwards, Ian H. Gilbert, David W. Gray (Lead / Corresponding author), Alan H. Fairlamb, Manu De Rycker (Lead / Corresponding author)

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Abstract

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.

Original languageEnglish
Pages (from-to)1044-1057
Number of pages14
JournalACS Infectious Diseases
Volume6
Issue number5
Early online date10 Apr 2020
DOIs
Publication statusPublished - 8 May 2020

Keywords

  • allosteric
  • drug discovery
  • inhibitor
  • kinetoplastid
  • Leishmania
  • methionyl-tRNA synthetase

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