Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases

Lang, Dorothy M.; Zemla, A. T.; Zhou, C. L. Ecale

Previous research found that Motif F occurs in all RdRps (38) , that it recognizes the incoming NTP (39) , serves as the primary fidelity checkpoint for RdRp and reorients the proper triphosphate into a position for efficient catalysis (40) . HmF is an extensive structure with surface exposure at both ends and near its mid-section at Motif F2 ( Figure 3A-D) . Motif F2 ( Figure 3E ) is analogous to the loop in hmG that varies in composition and length; it is upstream of a highly conserved motif and is speciesspecific. The large size of this homomorph and its positioning that transects the protein while maintaining contact with the template tunnel is consistent with its established role in transcription, which requires both fine-scale stability and large-scale mobility. Motif F3 consists of mostly basic amino acid residues and forms the roof of the NTP entry tunnel (41) ; the characteristic conserved arg residue is essential to nucleotide binding (38) . The required orientation of the F motifs would be stabilized by the loop formed by hmF and the doublestranded segment formed by the extension of the homomorph beyond the motifs. Both the N-terminal and C-terminal residues of the homomorph are exposed at the exterior surface of the protein. In PV, mutations of residues adjacent to the N-terminal are lethal: G149-i-I150 (42) and H149A/K150A (37) .