Abstract
A high-affinity divalent cation-binding site located proximal to the catalytic center has been identified in several RNA-dependent RNA polymerases (RdRps), but the characteristics of such a site have not been systematically studied. Here, all available polymerase structures that follow the hand-like structural motif were screened for the presence of a divalent cation close to the catalytic site but distinct from catalytic metal ions. Such non-catalytic ions were found in all RNA virus families for which there were high-resolution RdRp structures available. Bound ions were always located in structurally similar locations at an approximate 6-Å distance from the catalytic site. Furthermore, the second aspartate residue in the highly conserved GDD sequence was found to be involved in the coordination of the bound ion in all viral RdRps studied. These results suggest that a non-catalytic ion-binding site is conserved across positive-sense, single-stranded, and double-stranded RNA viruses. Interestingly, a non-catalytic ion was also observed in a similar position in the reverse transcriptase of the human immunodeficiency virus. Moreover, two members of the DNA-dependent DNA polymerase B family displayed an ion at a comparable distance from the catalytic site, but the position was clearly distinct from the non-catalytic ion-binding sites of RdRps.
Highlights
Viral RNA-dependent RNA polymerases are essential for the replication of RNA genomes and the transcription of viral messenger RNAs
It is possible that the PDB entries contain misannotations, we are confident that sporadic errors in one or a few of the structures do not have a significant effect on the overall results presented on the noncatalytic ions in Viral RNA-dependent RNA polymerases (vRdRps)
High-resolution Viral RNAdependent RNA polymerases (RdRps) Structures Currently, there are 193 high-resolution vRdRp structures available from 16 different viral species belonging to seven viral families (Table 2 and Table S1)
Summary
Viral RNA-dependent RNA polymerases (vRdRps) are essential for the replication of RNA genomes and the transcription of viral messenger RNAs (mRNAs). Like DNA-dependent DNA polymerases (DdDps) and the reverse transcriptases (RTs) of retroviruses, the vRdRps of double-stranded RNA (dsRNA) and singlestranded RNA (ssRNA) viruses with positive-sense genomes follow the canonical right-handed structure with fingers, palm, and thumb domains [1,2,3,4,5,6,7]. Six conserved structural motifs (A–F) have been identified in the vRdRps of dsRNA and positive-sense ssRNA viruses [7,8,9,10] Four of these motifs (A–D) are common to all hand-shaped polymerases [7,10] and are located in the palm domain, which consists of four antiparallel b-strands and two a-helices. Motifs E and F, which have been identified in vRdRps and RTs, are located at the boundary of the palm and thumb motifs and in the finger domain, respectively [8,15] (Fig. 1A)
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