The Ins and Outs of Viral RNA Polymerase Translocation

Central to the replication of RNA viruses is the RNA-dependent RNA polymerase (RdRp) [1], an important antiviral drug target [2–4]. RdRps belong to a large superfamily of template-directed nucleic acid polymerases, including DNA polymerases and reverse transcriptases [1]. These polymerases have a similar structural fold, which has been described as a “cupped right hand” with fingers, thumb and palm subdomains [5] (Fig. 1), and a similar chemical mechanism, involving at least two metal ions [6]. Polymerase function can be divided into three phases, including nucleotide selection, phosphodiester bond formation and translocation to the next templating nucleobase to prepare for the next round of nucleotide addition. Structural biology has provided tremendous insight into the structural changes that accompany each stage of catalysis for multiple classes of polymerases [7–10]. Least understood is how conformational changes in the polymerases may couple to translocation. In A-family DNA polymerases, a partial opening of the active site involving the temporary displacement of the “O-helix” and other regions in the fingers subdomain is likely important for movement along the DNA [11– 15]. Such a mechanism is unlikely to aid translocation in RdRps; these polymerases contain an extension of the fingers through the “fingertips” that interacts with the thumb domain, likely precluding a similar “opening” of the active site [16] (Fig. 1). In this issue, Sholders and Peersen have provided tantalizing insight into an alternative mechanism for translocation in RdRps, involving a palm structural motif known as “motif-B” [17]. Steric clashes between the motif-B loop and the template RNA may promote movement along the RNA to the next catalytic register. These findings are especially intriguing considering that the motif-B loop is involved in multiple stages of RdRp catalysis and