A Quantitative High-Resolution Genetic Profile Rapidly Identifies Sequence Determinants of Hepatitis C Viral Fitness and Drug Sensitivity
Figure 5
Critical residues mediating drug-protein interactions.
(A) 12 residues with altered drug sensitivity are aligned among 10 HCV strains representing 7 genotypes. The drug sensitivity on a genotype 2a background measured in our study, shown as fold change in relative fitness scores, is colored as (4A). For each strain, we predicted the EC50 by summing the drug sensitivity effect of residues at all 12 positions, and converting this into EC50 (Pred) according to the correlation in Fig. S4C. These predicted values compare well with observed EC50 (Obs) values previously determined by experiments [41]. (B) and (C) The drug-associated residues (resolved in structures) clustered together on the surface of the protein. Cartoon diagrams of three rotations of the domain I dimer with residues 54, 56, 58, 62, 75, 92 and 93 highlighted in yellow spheres on PDB structure 1ZH1 [37] (B) and 3FQM [48] (C). Position 21, 24, 28, 30 and 30 are in the helix/linker region, which is not annotated here.