Structural and catalytic properties of histidyl-tRNA synthetase: A potential drug target against leishmaniasis

Abstract

Visceral leishmaniasis is caused by Leishmania donovani which affects the poorer sections of society, and despite the global spread, effective treatment is unavailable. The current study investigates the potential of leishmanial histidyl-tRNA synthetase (LdHisRS) as a drug target. LdHisRS delineated more closeness to other protozoan parasites than its mammalian counterparts and contained relevant differences in the active site residues. The important ATP-binding residues were mutated to alanine and all the proteins, including human HisRS, were purified to homogeneity. LdHisRS exhibited a dimeric state in solution and showed maximal amino acid activation activity in physiological conditions. It also demonstrated a greater affinity for substrate over cofactor, while magnesium and potassium enhanced its activity better than other tested metal ions. Comp-7 m, a benzothiazolo-coumarin derivative, proved to be specific inhibitor of LdHisRS with competitive mode of inhibition for ATP whereas it displayed lower binding affinity towards mutants. LdHisRS majorly contained α-helices and most of the aromatic residues were present in its hydrophobic core. Additionally, Comp-7 m superimposed on ATP adenine ring during docking analysis and LdHisRS-ligand complexes had comparable stability as well as rigidity in molecular dynamics simulation. We thus provide structural and functional insights of LdHisRS which can be useful for devising antileishmanials.