7C2K

COVID-19 RNA-dependent RNA polymerase pre-translocated catalytic complex

Summary for 7C2K

• Entry DOI: 10.2210/pdb7c2k/pdb
• EMDB information: 30275
• Descriptor: RNA-directed RNA polymerase, Non-structural protein 8, Non-structural protein 7, ... (6 entities in total)
• Functional Keywords: covid-19, 2019-ncov, sars-cov-2, virus, rdrp, nsp12, nsp7, nsp8, rtc, cryo-em, viral protein, rna polymerase, drug target, antiviral, pre-translocated catalytic complex, viral protein-rna complex, viral protein/rna
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 6
• Total formula weight: 177127.99

Authors

Wang, Q.,Gao, Y.,Ji, W.,Mu, A.,Rao, Z. (deposition date: 2020-05-07, release date: 2020-06-03, Last modification date: 2024-11-13)

Primary citation

Wang, Q.,Wu, J.,Wang, H.,Gao, Y.,Liu, Q.,Mu, A.,Ji, W.,Yan, L.,Zhu, Y.,Zhu, C.,Fang, X.,Yang, X.,Huang, Y.,Gao, H.,Liu, F.,Ge, J.,Sun, Q.,Yang, X.,Xu, W.,Liu, Z.,Yang, H.,Lou, Z.,Jiang, B.,Guddat, L.W.,Gong, P.,Rao, Z.
Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Cell, 182:417-428.e13, 2020

PubMed Abstract: Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.

PubMed: 32526208
DOI: 10.1016/j.cell.2020.05.034

Experimental method

ELECTRON MICROSCOPY (2.93 Å)