English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Kokic, G., Hillen, H. S., Tegunov, D., Dienemann, C., Seitz, F., Schmitzova, J., et al. (2021). Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nature Communications, 12: 279. doi:10.1038/s41467-020-20542-0.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files
hide Files
:
3311510.pdf (Publisher version), 2MB
Name:
3311510.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-

Locators

show

Creators

show
hide
 Creators:
Kokic, G.1, Author              
Hillen, H. S.1, 2, Author              
Tegunov, D.1, Author              
Dienemann, C.1, Author              
Seitz, F., Author
Schmitzova, J.1, Author              
Farnung, L.1, Author              
Siewert, A., Author
Höbartner, C., Author
Cramer, P.1, Author              
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              
2Research Group Structure and Function of Molecular Machines, MPI for Biophysical Chemistry, Max Planck Society, ou_3265856              

Content

show
hide
Free keywords: Biochemistry; Cryoelectron microscopy; RNA
 Abstract: Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.

Details

show
hide
Language(s): eng - English
 Dates: 2021-01-12
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-020-20542-0
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Nature Communications
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: 7 Volume / Issue: 12 Sequence Number: 279 Start / End Page: - Identifier: -