Fig. 5: A model of the PfAsnRS-Asn-tRNA complex and compound docking reveal mechanisms for differential compound activity.
From: Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
A AlphaFold-Multimer model of the PfAsnRS dimer. Each chain of the dimer, and the long, disordered PfAsnRS-specific insert are depicted. B Upper panel shows a model of the PfAsnRS-Asn-tRNA complex, generated by overlay of the PfAsnRS model with the E. coli AspRS/tRNA(Asp) complex (PDB ID 1C0A31). The position of the bound ligand is highlighted with a dotted red line. Residue R487 (arrowed) lies close to the tRNA binding site. Lower panel shows a close-up view of the active site. Representative in silico docks of compounds to the PfAsnRS-Asn-tRNA model for (C) AMP, (D) AMS, (E) OSM-S-106 (see also Supplementary Fig. 12D), (F) OSM-E-32, and (G) OSM-S-488. Two orientations of each docked compound are shown to illustrate alignment of the reactive groups with the Asn-tRNA carbonyl carbon. The binding poses of AMP, AMS and OSM-S-106 are similar to the corresponding parts of our experimentally determined structures of the CDHsAsnRS/Asn-AMP, CDHsAsnRS/Asn-AMS, and CDHsAsnRS/Asn-OSM-S-106 complexes. The AMS sulfamate and the OSM-S-106 sulfonamide are in a suitable position to attack the carbonyl carbon of Asn-tRNA.
