Protein Translation Enzyme lysyl-tRNA Synthetase Presents a New Target for Drug Development against Causative Agents of Loiasis and Schistosomiasis
Fig 5
Cladosporin-binding mechanism of KRSs.
(A) Cladosporin binding in HsKRS (salmon) and LlKRS (green). Residues Ser346 and Val329 are replaced by larger Thr337 and Glu504 in HsKRS. Cladosporin bound to HsKRS structure is in blue and to LlKRS is in yellow. (B) Structural changes in apo-PfKRS (green) induced by cladosporin (CLD) and lysine (L-lys) individually are shown in blue and orange respectively. Cladosporin binding induces closing-in of the loop that contains motif 2, with rotameric adjustments in motif 2 residues Phe342, His338 and Arg559 (S1 Movie). This is accompanied by disulfide bond formation in the disordered loop (blue). L-lysine binding further induces a closing-in of mobile element present at roof of active site pocket and stabilization of the loop residues 580–590. The final PfKRS-CLD-K complex with all four major transitions is shown in orange. (C) HsKRS-CLD-K complex (cyan) overall conformation is similar to PfKRS-CLD-K complex (orange). The disulfide-stabilized loop is in an ordered helix in HsKRS. (D) LlKRS differs from previous KRS-cladosporin structures in that the incoming mobile roof and the disulfide regions are both disordered. Hence, cladosporin selectivity for P. falciparum, L. loa and perhaps S. mansoni KRSs is likely driven by the conserved residues Ser and Val that distally line active site pockets in these pathogen KRSs.