Discovery of an allosteric binding site in kinetoplastid methionyl-tRNA synthetase

DOI: 10.1021/acsinfecdis.9b00453

Authors: Leah S. Torrie (University of Dundee) , David A. Robinson (University of Dundee) , Michael G. Thomas (University of Dundee) , Judith V. Hobrath (University of Dundee) , Sharon M Shepherd (University of Dundee) , John M. Post (University of Dundee) , Eun-Jung Ko (University of Dundee) , Rafael Augusto Alves Ferreira (University of Dundee) , Claire J. Mackenzie (University of Dundee) , Karolina Wrobel (University of Dundee) , Darren Edwards (University of Dundee) , Ian H. Gilbert (University of Dundee) , David W. Gray (University of Dundee) , Alan H. Fairlamb (University of Dundee) , Manu De Rycker (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: April 2020
Diamond Proposal Number(s): 14980

Abstract: Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in the 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 (‘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 non-competitive mode of inhibition. Homology modelling 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 provides a novel strategy in the search for new therapeutics for kinetoplastid diseases.

Journal Keywords: Leishmania; kinetoplastid; methionyl-tRNA synthetase; drug discovery; allosteric; inhibitor

Diamond Keywords: Leishmaniasis; Chagas Disease; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 14/04/2020 11:01

Documents:
acsinfecdis.9b00453.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)