Fig. 6

Non-synonymous mutations in plasmepsin II and plasmepsin III. a Structural composition of plasmepsin II is shown as a ribbon diagram (top left panel). The N-terminal domain is shown in green and the C-terminal domain is shown in blue. The inter-domain β-sheet is located at the bottom of the structure, containing three β-strands from N-terminal and C-terminal domains. The orange β-hairpin forms the flap covering the active site. The catalytic dyad, Asp157 from the N-terminal domain and Asp337 from the C-terminal domain, are coloured in yellow. Plasmepsin II mutations are shown on the surface (bottom left panel) with colour intensity in pink shade representing allele frequency in Southeast Asia. Six mutations are clustered on the surface of plasmepsin II; D286N (1.4 %), Y141C and T154I (0.1 %), V133A, E145D and T289I (<0.1 %). Y141C was found exclusively in Southeast Asia. V133A, E145D, D286N, and T289I are from Southeast Asia and Africa. T154I was found in South Asia, Southeast Asia and Africa. Electrostatic potential surface of plasmepsin II reveals the large negative-charged patch (bottom right panel). The surface area contributed by D286 is marked by dashed circle. b Electrostatic potential surface of plasmepsin III (HAP) reveals large negative-charged patch (left panel). The surface area contributed by E173 is identified by dashed circle. Mutation E173V could be found with allele frequency <0.1 % in Southeast Asia and 0.1 % in West Africa. Mutation N411K (right panel, pink surface), which is a residue lining the substrate-binding cleft, is present only in Southeast Asia with the allele frequency of 0.1 %. The G233R mutation (right panel, purple surface) on the surface near substrate-binding cleft has allele frequency >20 % in Southeast Asia, South Asia and Papua New Guinea. Arginine at the position 233 was modelled and shown as purple stick. Pepstatin A is shown as black stick. Plasmepsin II structure was taken from PDB ID: 1XDH. HAP structure was taken from PDB ID: 3FNT