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Polymerases of paramyxoviruses and pneumoviruses - PubMed

  • ️Sun Jan 01 2017

Review

Polymerases of paramyxoviruses and pneumoviruses

Rachel Fearns et al. Virus Res. 2017.

Abstract

The paramyxo- and pneumoviruses are members of the order Mononegavirales, a group of viruses with non-segmented, negative strand RNA genomes. The polymerases of these viruses are multi-functional complexes, capable of transcribing subgenomic capped and polyadenylated mRNAs and replicating the genome. Although there is no native structure available for any complete paramyxo- or pneumovirus polymerase, functional and structural studies of a fragment of a pneumovirus polymerase protein and mutation analyses and resistance profiling of small-molecule inhibitors have generated a wealth of mechanistic information. This review integrates these data with the structure of a related polymerase, identifying similarities, differences, gaps in knowledge, and avenues for antiviral drug development.

Keywords: Capping; Inhibitor; Mononegavirales; Paramyxovirus; Pneumovirus; Polymerase.

Copyright © 2017 Elsevier B.V. All rights reserved.

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Conflict of interest statement

Conflicts of Interest

R.F.’s research is supported in part by sponsored research agreements with Alios Biopharma and Merck. R.K.P. is an inventor on US patent 8729059 “Paramyxovirus Family Inhibitors and Methods of Use Thereof”. This study could affect his personal financial status.

Figures

Figure 1
Figure 1. Schematic diagram showing the typical paramyxovirus or pneumovirus genome organization

The genes are shown as blue rectangles with gene start and gene end signals indicated with black and white rectangles, respectively. The leader (le) and trailer (tr) regions at the 3´ and 5´ ends of the genome, respectively, are indicated. The promoters at the 3´ ends of the genome and antigenome are shown with green arrows. The products of transcription and genome replication are represented below and above the genome, respectively. Transcription yields a short uncapped and non-polyadenylated RNA complementary to the leader, and mRNAs with 5´ caps and 3´ poly A tails, corresponding to each of the genes. Replication yields antigenome and genome RNAs that are encapsidated with N protein (grey circles).

Figure 2
Figure 2. Structure of an nsNSV polymerase

(A) Linear representation of the VSV L protein, indicating the positions of conserved regions I-VI relative to the different domains. (B) Views of the VSV L protein structure (PDB 5a22) (8). The domains identified by Liang et al are as follows: RdRP (blue), capping (green), connector domain (yellow), methyltransferase domain (orange) and C-terminal domain (red).

Figure 3
Figure 3. The RdRp domain

(A) In the left panel, the RdRp active site within the VSV L protein is shown, with the motifs A-D and the putative priming loop colored gold. The right panel shows the same image with residues that correspond to inhibitory substitutions in Sendai virus L shown in magenta. (B) A wider view of the image shown in panel A, from the perspective of looking through the template entry site. Corresponding amino acids were made by aligning Sendai and measles virus L protein sequences and referring to the alignment presented by Liang et al (8).

Figure 4
Figure 4. The capping domain

The capping domain of the VSV L protein is shown with residues essential for capping activity indicated in gold. Residues that correspond to positions of capping inhibitor resistance mutations are shown in red; residues that correspond to substitutions that inhibit Sendai virus transcription, but not replication, are shown in magenta.

Figure 5
Figure 5. The methyltransferase domain

The methyltransferase and C-terminal domain of the HMPV L protein (PDB 4UCI) is shown, with domains colored as in Figure 2. Residues that are required for methyltransferase activity are shown in magenta with the K-D-K-E residues in a lighter shade. S-adenosyl methionine is shown in black, and GTP (which represents the RNA substrate) in grey.

Figure 6
Figure 6. Comparison of paramyxo- and pneumovirus promoters

The sequences at the 3´ end of the representative paramyxo- and pneumovirus leader promoters are shown, with uracil residues colored in red. The sequences are aligned with the likely initiation site in the paramyxovirus promoters (position 1) opposite the dominant initiation site in the pneumovirus promoters (position 3) to illustrate the alignment of uracil residues in most of the promoters. Abbreviations are Atlantic salmon paramyxovirus (ASPV), Newcastle disease virus (NDV), Fer de Lance virus (FDLV), measles virus (MeV), and mumps virus (MuV).

Figure 7
Figure 7. Substitutions that may inhibit polymerase rearrangement

The VSV L protein with RdRP, capping and methyltransferase domains is shown. The RdRp is in pale blue with the active site (viewed through the template entry channel) and putative priming loop colored gold. The capping domain is colored green and the methyltransferase in orange. Residues corresponding to substitutions that inhibit both transcription and replication in Sendai virus, that are distant from the RdRp active site are shown in magenta.

Figure 8
Figure 8. Substitutions that inhibit transcription termination at the gene end signal

The VSV L protein is shown, colored as in Figure 2. Residues corresponding to substitutions in RSV L protein that inhibit mRNA release at a gene end signal are shown as magenta spheres.

Figure 9
Figure 9. Substitutions that inhibit RNA replication specifically

The VSV L protein is shown, colored as in Figure 2. Residues corresponding to substitutions in Sendai virus L protein that inhibit replication, but not transcription, are shown in magenta.

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