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

The polymerase protein family has been studied extensively for >40 years. This interest has been motivated by their unique function-to replicate all forms of life, and confounded by their sequence diversity. As more tertiary structures of polymerase were solved, it became apparent that widely diverse sequences form highly similar structures. There has not, until recently, been a time-effective computational method to make detailed comparisons of these observations. The objective of this study was to clarify the relationship between structure and sequence in a group of RNA-dependent RNA polymerases (RdRps) that replicate many of the viruses that represent significant threats to life throughout the world. We selected well-studied species in order to maximize the amount of experimental data that could be used to evaluate the association of functional residues and structure (Table 1) . We used the StralSV algorithm (1) to perform structure comparisons between all of the selected species. We created maps of residue-to-residue (R2R) correspondence from which we determined the boundaries of structurally similar segments-which we named 'homomorphs'. In contrast to the relatively short lengths of previously described motifs, we found that most homomorphs are long, and each provides a structural connection between the template tunnel or NTP entry tunnel and the exterior of the protein.