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. 2014 Apr 23;4:4765. doi: 10.1038/srep04765

Figure 8. Docking of inhibitors and mapping of drug resistance and genotype variation onto the alternate NS5A1–191 dimer models.

Figure 8

The same monomer colour scheme is used as in Figs. 1 and 7. (a) The 1ZH1 dimer model. BMS-790052 (blue sticks) has been docked into a pocket at the dimer interface formed by the concave protein surface (where Y93 is located) and the two flexible loops consisting of residues 26–32. The locations of resistance mutation residues (red sticks) and genotype difference residues (green sticks) around the putative inhibitor binding site are indicated. (b) The 1ZH1 dimer model shown as a molecular surface, known resistance mutation residues are coloured red. View is a rotation of −90° about the X-axis from that shown in (a) looking directly down onto the pocket at the dimer interface. BMS-790052 depicted as blue and red cpk. (c) AZD7295 (blue, red and cyan cpk) docked into the 3FQQ dimer model (shown as a molecular surface; same view of NS5A1–191 as shown in Fig. 7b). Known resistance mutation residues are in red. (d) Model of the 3FQQ dimer Y93H resistance mutation with BMS-790052 docked (blue and red sticks). Showing a close up view of Y93 (red sticks) in wild type and the mutated residue Y93H (grey and blue sticks). Dashed lines indicate possible hydrogen bonds. (e) Close up view of the 3FQQ dimer model hydrophobic pocket. There are two of these hydrophobic pockets in the 3FQQ dimer model, located at each end of the cleft formed by the monomer-monomer interface. BMS-790052 shown as blue, red and white cpk. NS5A1–191 shown as cartoon and transparent molecular surface. Side-chains of residues depicted in stick format. (f) Same orientation of BMS-790052 (blue sticks) docked into the 3FQQ dimer model as shown in Fig. 7b; NS5A depicted as a transparent cartoon. The side-chains of resistance mutation residues (red sticks) and genotype difference residues (green sticks) around the putative inhibitor binding site are shown. Other residues interacting with the compound are shown as grey sticks. * denotes residues from the yellow monomer.