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Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex.

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Malone B, Chen J, Wang Q, Llewellyn E, Choi YJ, Olinares PDB, Cao X, Hernandez C, Eng ET, Chait BT, Shaw DE, Landick R, Darst SA, Campbell EA
OpenAccess logo Proc Natl Acad Sci U S A 118 (2021)
Related entries: 7krn, 7kro

Cited: 53 times
EuropePMC logo PMID: 33883267

Abstract

Backtracking, the reverse motion of the transcriptase enzyme on the nucleic acid template, is a universal regulatory feature of transcription in cellular organisms but its role in viruses is not established. Here we present evidence that backtracking extends into the viral realm, where backtracking by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) may aid viral transcription and replication. Structures of SARS-CoV-2 RdRp bound to the essential nsp13 helicase and RNA suggested the helicase facilitates backtracking. We use cryo-electron microscopy, RNA-protein cross-linking, and unbiased molecular dynamics simulations to characterize SARS-CoV-2 RdRp backtracking. The results establish that the single-stranded 3' segment of the product RNA generated by backtracking extrudes through the RdRp nucleoside triphosphate (NTP) entry tunnel, that a mismatched nucleotide at the product RNA 3' end frays and enters the NTP entry tunnel to initiate backtracking, and that nsp13 stimulates RdRp backtracking. Backtracking may aid proofreading, a crucial process for SARS-CoV-2 resistance against antivirals.

Reviews - 7krp mentioned but not cited (2)

  1. Structure and function of SARS-CoV-2 polymerase. Hillen HS. Curr Opin Virol 48 82-90 (2021)
  2. Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies. Ramaswamy K, Rashid M, Ramasamy S, Jayavelu T, Venkataraman S. Viruses 14 2200 (2022)

Articles - 7krp mentioned but not cited (4)

  1. Insights into Binding of Single-Stranded Viral RNA Template to the Replication-Transcription Complex of SARS-CoV-2 for the Priming Reaction from Molecular Dynamics Simulations. Wang J, Shi Y, Reiss K, Allen B, Maschietto F, Lolis E, Konigsberg WH, Lisi GP, Batista VS. Biochemistry 61 424-432 (2022)
  2. Significant Broad-Spectrum Antiviral Activity of Bi121 against Different Variants of SARS-CoV-2. Subhadra B, Agrawal R, Pal VK, Chenine AL, Mattathil JG, Singh A. Viruses 15 1299 (2023)
  3. research-article Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex. Malone B, Chen J, Wang Q, Llewellyn E, Choi YJ, Olinares PDB, Cao X, Hernandez C, Eng ET, Chait BT, Shaw DE, Landick R, Darst SA, Campbell EA. bioRxiv 2021.03.13.435256 (2021)
  4. research-article An alphacoronavirus polymerase structure reveals conserved co-factor functions. Anderson TK, Hoferle PJ, Lee KW, Coon JJ, Kirchdoerfer RN. bioRxiv 2023.03.15.532841 (2023)


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  5. A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Shannon A, Fattorini V, Sama B, Selisko B, Feracci M, Falcou C, Gauffre P, El Kazzi P, Delpal A, Decroly E, Alvarez K, Eydoux C, Guillemot JC, Moussa A, Good SS, La Colla P, Lin K, Sommadossi JP, Zhu Y, Yan X, Shi H, Ferron F, Canard B. Nat Commun 13 621 (2022)
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