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

Brandon F. Malone, Jason K. Perry, Paul Dominic B. Olinares, Hery W. Lee, James Chen, Todd C. Appleby, Joy Y. Feng, John P. Bilello, Honkit Ng, Johanna Sotiris, Mark Ebrahim, Eugene Y. D. Chua, Joshua H. Mendez, Ed T. Eng, Robert Landick, Matthias Götte, Brian T. Chait, Elizabeth A. Campbell () and Seth A. Darst ()
Additional contact information
Brandon F. Malone: The Rockefeller University
Jason K. Perry: Gilead Sciences, Inc.
Paul Dominic B. Olinares: The Rockefeller University
Hery W. Lee: University of Alberta
James Chen: The Rockefeller University
Todd C. Appleby: Gilead Sciences, Inc.
Joy Y. Feng: Gilead Sciences, Inc.
John P. Bilello: Gilead Sciences, Inc.
Honkit Ng: The Rockefeller University
Johanna Sotiris: The Rockefeller University
Mark Ebrahim: The Rockefeller University
Eugene Y. D. Chua: New York Structural Biology Center
Joshua H. Mendez: New York Structural Biology Center
Ed T. Eng: New York Structural Biology Center
Robert Landick: University of Wisconsin-Madison
Matthias Götte: University of Alberta
Brian T. Chait: The Rockefeller University
Elizabeth A. Campbell: The Rockefeller University
Seth A. Darst: The Rockefeller University

Nature, 2023, vol. 614, issue 7949, 781-787

Abstract: Abstract 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 remdesivir2. 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 triphosphate3,4. 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 propagation5. The NiRAN selectively binds guanosine triphosphate, strengthening proposals for the role of this domain in the formation of the 5′ RNA cap6.

Date: 2023
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DOI: 10.1038/s41586-022-05664-3

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