Structure, Dynamics, and Fidelity of RNA-Dependent RNA Polymerases

摘要: The RNA-dependent RNA polymerase (RdRp) is responsible for replicating the genomes of viruses. overall structure and function RdRps similar to other nucleic acid polymerases, although some employ unique initiation mechanisms. Recent biophysical studies indicate that internal motions RdRps, are critical their catalytic fidelity. In particular, these have suggested closing active site in preparation catalysis involves movement motif-D loop help reposition a highly conserved lysine, enabling this residue act as general protonate pyrophosphate leaving group. Binding incorrect nucleoside triphosphate does not induce same structural changes loop, indicating role nucleotide discrimination. Indeed, substitution at lysine increases fidelity and, intriguingly, decreases viral pathogenesis. nature thus suggests universal mechanism rational vaccine design based on generating variants position. Moreover, substitutions elsewhere RdRp structure, including those remote from site, likewise lead decrease cases, amino alter protein (including loop) without substantially affecting structure. A picture emerges which polymerases can be viewed “small world” networks acids; communication pathways connect surface all way center. These impacted by substitutions, inhibitor binding, and/or binding accessory replication proteins regulate