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Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex.
Malone, Brandon; Chen, James; Wang, Qi; Llewellyn, Eliza; Choi, Young Joo; Olinares, Paul Dominic B; Cao, Xinyun; Hernandez, Carolina; Eng, Edward T; Chait, Brian T; Shaw, David E; Landick, Robert; Darst, Seth A; Campbell, Elizabeth A.
  • Malone B; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10065.
  • Chen J; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10065.
  • Wang Q; D. E. Shaw Research, New York, NY 10036.
  • Llewellyn E; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10065.
  • Choi YJ; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10065.
  • Olinares PDB; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, 10065.
  • Cao X; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.
  • Hernandez C; The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027.
  • Eng ET; The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027.
  • Chait BT; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, 10065.
  • Shaw DE; D. E. Shaw Research, New York, NY 10036.
  • Landick R; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.
  • Darst SA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.
  • Campbell EA; Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1254144
Preprint
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Semantic information from SemMedBD (by NLM)
1. Virus LOCATION_OF Transcriptase
Subject
Virus
Predicate
LOCATION_OF
Object
Transcriptase
2. cellular organisms LOCATION_OF Transcriptase
Subject
cellular organisms
Predicate
LOCATION_OF
Object
Transcriptase
3. Virus LOCATION_OF Transcriptase
Subject
Virus
Predicate
LOCATION_OF
Object
Transcriptase
4. cellular organisms LOCATION_OF Transcriptase
Subject
cellular organisms
Predicate
LOCATION_OF
Object
Transcriptase
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / SARS-CoV-2 / COVID-19 Type of study: Randomized controlled trials Limits: Humans Language: English Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / SARS-CoV-2 / COVID-19 Type of study: Randomized controlled trials Limits: Humans Language: English Year: 2021 Document Type: Article