Fig. 5: Conformational changes induced by the β6A117D mutation.

a, b The EM densities of the β6 subunit around the Ala117 region in the WT (a) and in the A117D mutant Pf20S structure (b). c Conformational changes induced by the β6A117D mutation. The 6-residue peptide G156-S157-Y158-C159-E160-A161 flips upside down to prevent Tyr158 from clashing with the charged and bulky Asp117. d The A117D mutation forces Tyr158 to swing 150° and insert into the S3 site of the β5 catalytic pocket, where the residue clashes with the P3 morpholino group of TDI-8304. e Ser154 moves away and loses interaction with the TDI-8304 pyrrolidinone in the A117D mutant β6. The clash with the morpholino group and the loss of interaction with the pyrrolidinone likely explain the reduced β5 inhibition of the mutant Pf20S, and therefore, the parasite’s resistance to TDI-8304. f Detailed interactions of WLW-vs in the β2 catalytic pocket. Several hydrophobic residues surrounding the morpholino and the indole groups are in black. g Detailed interactions of WLW-vs in the β5 catalytic pocket. In the mutant structure, the β6 Tyr158 flips over to interact with the inhibitor indole group at the S3 site and create a hydrophobic environment. h Offset π-π stacking between the indole ring of WLW-vs and the hydroxyphenyl group of Tyr158.