Conformational heterogeneity of Flaviviridae polymerase structure may be related to in cis regulations. (a) Representative Flaviviridae polymerase structure adopting the canonical conformations (pdb entries: JEV/4K6M, BVDV/1S4F, HCV/1NB4); (b) Disorder and/or alternative folding of motifs F and G observed in Flaviviridae polymerases (pdb entries: JEV-ii/4MTP [60], JEV-iii/4HDG, WNV/2HFZ, DENV/4V0Q, DENV-ii/2J7U, BVDV-ii/2CJQ). Motifs F and G are shown as thick noodles and the pinky finger residues flanking motif G are shown as thin noodles. Note that in the apo JEV RdRP structure (JEV-ii) and GTP-bound JEV RdRP structure, the NTP entry channel is blocked by the non-canonically folded motif F. Color coding is as in Figure 1b and Figure 3b. A 4 nt RNA template, a dinucleotide primer, and an ADP molecule taken from an HCV IC structure (pdb entry: 4WTJ) were modeled into all structures for comparison. The α-carbons of JEV NS5 residues 409–410 in motif G and 459, 461, 474 in motif F and their equivalents in other polymerases are shown as spheres to help distinguish canonical and alternative folding of these two motifs. Double arrows are used to connect polymerases from the same viral species or from the same genus. The MTase in the full-length Flavivirus NS5 structures are shown as surface representations. Structure superimpositions were carried out as in Figure 1b.
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