Structural basis for substrate selection by the SARS-CoV-2 replicase.

Autor: Malone BF; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA., Perry JK; Gilead Sciences, Inc., Foster City, CA, USA., Olinares PDB; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, USA., Lee HW; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada., Chen J; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA.; Department of Cell Biology, New York University School of Medicine, New York, NY, USA., Appleby TC; Gilead Sciences, Inc., Foster City, CA, USA., Feng JY; Gilead Sciences, Inc., Foster City, CA, USA., Bilello JP; Gilead Sciences, Inc., Foster City, CA, USA., Ng H; The Evelyn Gruss Lipper Cryo-Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA., Sotiris J; The Evelyn Gruss Lipper Cryo-Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA., Ebrahim M; The Evelyn Gruss Lipper Cryo-Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA., Chua EYD; National Center for Cryo-EM Access and Training, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA., Mendez JH; National Center for Cryo-EM Access and Training, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA., Eng ET; National Center for Cryo-EM Access and Training, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA., Landick R; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., Götte M; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada., Chait BT; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, USA., Campbell EA; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA. campbee@rockefeller.edu., Darst SA; Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA. darst@rockefeller.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Feb; Vol. 614 (7949), pp. 781-787. Date of Electronic Publication: 2023 Feb 01.
DOI: 10.1038/s41586-022-05664-3
Abstrakt: The SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication-transcription complex (RTC) 1 . Accordingly, the RTC is a target for clinically approved antiviral nucleoside analogues, including remdesivir 2 . Faithful synthesis of viral RNAs by the RTC requires recognition of the correct nucleotide triphosphate (NTP) for incorporation into the nascent RNA. To be effective inhibitors, antiviral nucleoside analogues must compete with the natural NTPs for incorporation. How the SARS-CoV-2 RTC discriminates between the natural NTPs, and how antiviral nucleoside analogues compete, has not been discerned in detail. Here, we use cryogenic-electron microscopy to visualize the RTC bound to each of the natural NTPs in states poised for incorporation. Furthermore, we investigate the RTC with the active metabolite of remdesivir, remdesivir triphosphate (RDV-TP), highlighting the structural basis for the selective incorporation of RDV-TP over its natural counterpart adenosine triphosphate 3,4 . Our results explain the suite of interactions required for NTP recognition, informing the rational design of antivirals. Our analysis also yields insights into nucleotide recognition by the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase), an enigmatic catalytic domain essential for viral propagation 5 . The NiRAN selectively binds guanosine triphosphate, strengthening proposals for the role of this domain in the formation of the 5' RNA cap 6 .
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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