Figure 5. Selective inhibition of Pf  TrpRS^api but not Pf  TrpRS^cyt by indolmycin.

(a) Inhibition of tRNA^trp formation by Pf  TrpRS^api (shown in green) and Pf  TrpRS^cyt (shown in red) was tested at increasing concentrations of indolmycin. Pf  TrpRS^api is completely inhibited at higher concentrations, Pf  TrpRS^cyt is comparatively insensitive. (b) Surface representation of chain A of the crystal structure of P. falciparum cytosolic TrpRS with bound 5′AMP•tryptophan-indolmycin overlay (PDB: 4J75; shown in magenta) and (c) cartoon representations of the protein superimposed with chain A of the crystal structure of B. stearothermophilus TrpRS with bound ATP•Mg²⁺•indolmycin (PDB: 5DK4; shown in violet). (d) Zoom-in view of ATP•Mg²⁺•indolmycin-tryptophan overlay in the catalytic core of TrpRS. Surface (e) and cartoon (f ) representations of P. falciparum apicoplast TrpRS with bound ATP•Mg²⁺•indolmycin. Note that the iTasser C-score for this model is low (−2.5), indicating global model low quality, although manual inspection indicates a good structural fit in the tryptophan binding region. (g) Zoom-in view of ATP•Mg²⁺•indolmycin in the conserved catalytic core of TrpRS. A number of residues within the active site were made transparent to show the ligand and relevant interacting residues. The substrates are shown as sticks. ATP substrates are shown in white, tryptophan is shown in green, and indolmycin is shown in yellow.