Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors

By R. Kirchdoerfer, A. Ward. Nature Communications, 2019

794 citations recorded by the source corpus.

Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics. The pathogenic human coronaviruses SARS- and MERS-CoV can cause severe respiratory disease. Here the authors present the 3.1Å cryo-EM structure of the SARS-CoV RNA polymerase nsp12 bound to its essential co-factors nsp7 and nsp8, which is of interest for antiviral drug development.

Subfields: Cardiology and Cardiovascular Medicine, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/7fd0972f4d5eb0e4c7ec68efad48fc01a1f547c2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cardiology and Cardiovascular Medicine

1. Calvin J. Gordon
2. D. Porter
3. M. Götte
4. Joy Y. Feng
5. E. Tchesnokov
6. Abdo A. Elfiky

In Infectious Diseases

1. Calvin J. Gordon
2. D. Porter
3. M. Götte
4. Joy Y. Feng
5. E. Tchesnokov
6. Abdo A. Elfiky

Citations in the corpus

• Genomic characterization of a novel SARS-CoV-2 (2020, background): “Numerous investigations have depicted that ORFs and ACE2 genes play a key role during novel coronavirus disease (Koyama et al., 2020; Kirchdoerfer and Ward, 2019; Van der Meer et al., 1998; Wan et al., 2020).”
• Pfam: The protein families database in 2021 (2020, background): “NSP12 is an RNA-directed RNA polymerase described in two entries, Pfam:PF06478 and Pfam:PF00680 describing the N-and C-terminal domains, respectively (16).”
• Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency (2020, methodology): “This model is based on the cryo-EM structure of the apo SARS-Co RdRp complex composed of nsp7, nsp8, and nsp12 (19).”
• An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice (2020, neutral): “3A onto the structure of the SARS-CoV RdRp ( 20 ) (Fig.”
• Structure of the RNA-dependent RNA polymerase from COVID-19 virus (2020, methodology): “Model building and refinement To solve the structure of the COVID-19 virus nsp12-nsp7-nsp8 complex, the structure of the SARS-CoV nsp12 (9) and nsp7-8 (21) were individually placed and rigid-body fitted into the cryoEM map using UCSF Chimera (22).”
• Structure of replicating SARS-CoV-2 polymerase (2020, background): “Subunit nsp7 binds to the thumb, whereas two copies of nsp8 bind to the fingers and thumb subdomains 16, 17 .”
• Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir (2020, background): “Purification of the RdRp complex For nsp7 or nsp8 expressed in bacterial, the purification was similar to the purification of nsp7 and nsp8 reported before(13).”
• Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV (2020, background): “site (Figure 3B).(23) This high sequence conservation between the two enzymes makes it highly”
• The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus (2020, methodology): “Broad spectrum antivirals or compounds with demonstrated activity against SARS–CoV orMERS–CoV are now considered for the treatment of infection caused by the novel coronavirus SARS–CoV-2.”
• Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study (2020, background): “1 Å resolution, which was deposited in the protein data bank in 2019 [32].”
• SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective (2020, methodology): “SARS HCoV solved structure (PDB ID: 6NUR, chain A) is used as a template (97.08% identity) (Kirchdoerfer & Ward, 2019).”
• Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 (2020, neutral): “1 Å resolution deposited in the protein data bank last year [35].”