Crystal structures of Entamoeba histolytica lysyl‐tRNA synthetase reveal conformational changes upon lysine binding and a specific helix bundle domain

Abstract

Edited by M. Ibba Keywords:Lysyl-tRNA synthetase L-Lysine Adenosine triphosphate AMPPNP Lysyl-adenylate a b s t r a c tThe class II lysyl-tRNA synthetases (KRS) are conserved aminoacyl-tRNA synthetases that attach lysine to the cognate tRNA in a two-step mechanism. The enzyme from the parasitic protozoan Entamoeba histolytica was crystallized in the presence of small ligands to generate snapshots of the lysine-adenylate formation. The residues involved in lysine activation are highly conserved and the active site closes around the lysyl-adenylate, as observed in bacterial KRS. The Entamoeba EMAPII-like polypeptide is not resolved in the crystals, but another Entamoeba-specific insertion could be modeled as a small helix bundle that may contribute to tRNA binding through interaction with the tRNA hinge.

Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development

“…Cladosporin targets the cytosolic lysyl-tRNA synthetase (LysRS), as parasites that overexpress LysRS are resistant to cladosporin ( 47 ). The apo structure of LysRS from Entamoeba histolytica in a complex with small ligands shows that conformational changes occur upon lysine binding in the catalytic domain, similar to the earlier reports on bacterial LysRS structures ( 48 ). Three-dimensional structures of Pf LysRS in apo form and complex with substrates show cladosporin interacting with the ATP-binding site as it mimics the natural substrate adenosine ( 49 , 50 ).…”

Characterization of association of human mitochondrial lysyl-tRNA synthetase with HIV-1 Pol and tRNA3Lys

“…8 ). The structural organization of this peptide in human LysRS is not known, but could be similar to that observed for the equivalent peptide in Entamoeba histolytica LysRS [ 33 ]. In the crystal structure reported for this enzyme crystallized in the absence of tRNA, this peptide adopts an α-helix conformation.…”

“…In the crystal structure reported for this enzyme crystallized in the absence of tRNA, this peptide adopts an α-helix conformation. However, the place occupied by this peptide in the crystal is not compatible with the binding of a tRNA molecule [ 33 ]. This suggests that this peptide is mobile and may adopt different conformations relative to the core enzyme, in the absence or in the presence of a tRNA molecule.…”