6SWX

Leishmania major methionyl-tRNA synthetase in complex with an allosteric inhibitor

Summary for 6SWX

• Entry DOI: 10.2210/pdb6swx/pdb
• Descriptor: Putative methionyl-tRNA synthetase, methyl 2-[[6-[[3,4-bis(fluoranyl)phenyl]amino]-1-methyl-pyrazolo[3,4-d]pyrimidin-4-yl]amino]ethanoate, METHIONINE, ... (4 entities in total)
• Functional Keywords: leishmania, parasite, aminoacyl-trna synthetase, trna ligase, aars, metrs, methionine, translation, atp-binding, nucleotide-binding, ligase, drug discovery, dundee drug discovery unit
• Biological source: Leishmania major
• Total number of polymer chains: 1
• Total formula weight: 64482.31

Authors

Robinson, D.A.,Torrie, L.S.,Shepherd, S.M.,De Rycker, M.,Thomas, M.G.,Wyatt, P.G. (deposition date: 2019-09-24, release date: 2020-08-05, Last modification date: 2024-01-24)

Primary citation

Torrie, L.S.,Robinson, D.A.,Thomas, M.G.,Hobrath, J.V.,Shepherd, S.M.,Post, J.M.,Ko, E.J.,Ferreira, R.A.,Mackenzie, C.J.,Wrobel, K.,Edwards, D.P.,Gilbert, I.H.,Gray, D.W.,Fairlamb, A.H.,De Rycker, M.
Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.
Acs Infect Dis., 6:1044-1057, 2020

PubMed Abstract: Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites and . 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 MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the MetRS enzyme revealed key differences in the allosteric pocket between the and enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the enzyme compared to the 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.

PubMed: 32275825
DOI: 10.1021/acsinfecdis.9b00453

Experimental method

X-RAY DIFFRACTION (1.95 Å)