7OZU

SARS-CoV-2 RdRp with Molnupiravir/ NHC in the template strand base-paired with A

Summary for 7OZU

• Entry DOI: 10.2210/pdb7ozu/pdb
• EMDB information: 13135
• Descriptor: Replicase polyprotein 1ab, Non-structural protein 8, Non-structural protein 7, ... (6 entities in total)
• Functional Keywords: sars-cov-2, rna-dependent rna polymerase, molnupiravir (nhc), viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2); More
• Total number of polymer chains: 5
• Total formula weight: 161134.37

Authors

Kabinger, F.,Stiller, C.,Schmitzova, J.,Dienemann, C.,Kokic, G.,Hillen, H.S.,Hoebartner, C.,Cramer, P. (deposition date: 2021-06-28, release date: 2021-08-18, Last modification date: 2024-07-17)

Primary citation

Kabinger, F.,Stiller, C.,Schmitzova, J.,Dienemann, C.,Kokic, G.,Hillen, H.S.,Hobartner, C.,Cramer, P.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat.Struct.Mol.Biol., 28:740-746, 2021

PubMed Abstract: Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β-D-N-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp-RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.

PubMed: 34381216
DOI: 10.1038/s41594-021-00651-0

Experimental method

ELECTRON MICROSCOPY (3.3 Å)